Pyrrolotriazinone Derivatives As PI3K Inhibitors - DocsLib

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(11) EP 2 518 070 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 31.10.2012 Bulletin 2012/44 C07D 473/34 (2006.01) C07D 487/04 (2006.01) A61K 31/4985 (2006.01) A61K 31/437 (2006.01) (2006.01) (21) Application number: 11382124.3 A61P 35/00

(22) Date of filing: 29.04.2011

(84) Designated Contracting States: • Caturla Javaloyes, Juan Francisco AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 08980, Sant Feliu de Llobregat (ES) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • Gracia Ferrer, Jordi PL PT RO RS SE SI SK SM TR 08980, Sant Feliu de Llobregat (ES) Designated Extension States: • Matassa, Victor Giulio BA ME 08980, Sant Feliu de Llobregat (ES) • Terricabras Belart, Emma (71) Applicant: Almirall, S.A. 08980, Sant Feliu de Llobregat (ES) 08022 Barcelona (ES) (74) Representative: Elzaburu Marquez, Alberto (72) Inventors: Elzaburu S.L.P. • Bernal Anchuela, Francisco Javier Miguel Angel 21 08980, Sant Feliu de Llobregat (ES) 28010 Madrid (ES) • Carrascal Riera, Marta 08980, Sant Feliu de Llobregat (ES)

(54) Pyrrolotriazinone derivatives as PI3K inhibitors

(57) New pyrrolotriazinone derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks) EP 2 518 070 A1

Printed by Jouve, 75001 PARIS (FR) EP 2 518 070 A1

Description

[0001] When cells are activated by extracellular stimuli, intracellular signalling cascades involving the regulation of second messengers are initiated that eventually produce a response of the cell to the stimuli. Phosphoinositide 3- Kinases 5 (PI3Ks) are among the enzymes involved in early signalling events to a plethora of different types of stimuli. PI3Ks phosphorylate the 3-hydroxyl group of the inositol ring of phosphatidylinositol (PtdIns), Ptdlns-4- phosphate (PtdIns4P), and Ptdlns-4,5-bisphosphate (PtdIns(4,5)P2). The resulting 3-phosphoinositides mediate correct localization and subsequent activation of a number of downstream effector proteins that bind to the lipids via specific lipid binding sequences such as the pleckstrin homology (PH) domain (Vanhaesebroeck B, 2010, Nat Rev Mol Cell Biol 5:11381-6). 10 [0002] The PI3K family is divided into 3 different classes (PI3K class I, class II, and class III), depending on substrate preference and structural features. [0003] The best characterized is the PI3K class I with the preferential substrate Ptdlns-(4,5) P2. It englobes 4 different isoforms which originally were further subdivided into class IA (p110a, p110b, p110d), binding to a p85 type of regulatory subunit, and class IB (p110g) which is regulated by p101 and p87 subunits. Whereas p110a (PI3Ka or PI3K α) and p110b 15 (Pl3Kb or PI3Kβ) isoforms are expressed ubiquitously, p110g (PI3Kg or PI3Kγ) and especially p110d (PI3Kd or PI3Kδ) have a more restricted expression pattern and seem to play a major role in leukocytes (Kok K, Trends Biochem Science 34:115-127, 2009). [0004] Both, PI3Kd and PI3Kg are involved in activation of immune cells by a large variety of different stimuli. Phar- macological inhibition or genetic deficiency in active p110d has been shown to inhibit T cell proliferation and cytokine 20 production in response to different stimuli such as anti- CD3, anti-CD3/CD28, superantigen or antigen in vitro (Ji H, Blood 2007; Okkenhaug K, Science 2002; Garcon F, 2009; Soond DR, Blood 2010; Herman SEM, Blood June 3, 2010; William O, Chemistry & Biology 17, 2010) and to suppress concanavalin A and anti-CD3 induced cytokine production as well as antigen-dependent tissue retention in vivo (Soond DR, Blood 2010; Jarmin SJ, JCI 2008). In addition, B cell function is critically dependent on functional PI3Kd activity as demonstrated by suppressed B cell proliferation and cytokine 25 release in vitro in response to anti-IgM (Bilancio A, Blood 107, 2006), toll like receptor agonists such as LPS and oligodeoxynucleotides (Dil N, Mol Immunol 46, 2009) or impaired ability to stimulate antigen-specific T cells (Al-Alwan M, JI 2007) in the absence of functional p110d or pharmacological inhibition. In vivo, PI3Kg deficient mice display partially suppressed antibody production upon immunization (Garcon F, 2009; Durand CA, JI 2009). Further studies have demonstrated an important role of PI3Kd in inhibition of T cell apoptosis and in TH17 differentiation (Haylock-Jacobs S, J. 30 Autoimmun 2010). [0005] In addition, mast cell degranulation was reduced in cells from mice with inactivated PI3Kd or by pharmacological inhibition of PI3Kd (Ali K, Nature 431: 1007-1011, 2004; Ali K, Journal of Immunology 180: 2538-2544, 2008) and basophil activation via the FcE receptor is suppressed by pharmacological inhibition of PI3Kd (Lannutti BJ, Blood Oct. 2010). [0006] In terms of neutrophil function, PI3Kd inhibition inhibits migration of mouse neutrophils to fMLP in an under- 35 agarose migration assay by inhibiting cell polarization and directional movement (Sadhu C, JI 170, 2003) and mouse PI3Kd deficient or inhibitor treated neutrophils show slightly (25%) reduced in vitro chemotaxis to LTB4, whereas in vivo accumulation in the lung in response to LPS was reduced by more than 80%, indicating an important role of PI3Kd in endothelial cells for mediating PMN transendothelial migration (Puri KD, Blood 103, 2004). Furthermore, TNF induced neutrophil infiltration to an air pouch in mice and elastase release is partially inhibited by a PI3Kd selective inhibitor 40 (Sadhu C, Biochem Biophys Res Comm 308, 2003). In addition, TNF mediated priming of oxidative burst by human neutrophils depends on PI3Kd activity (Condliffe AM, Blood 106, 2005). [0007] In contrast to the dominant role of PI3Kd in lymphocyte activation, PI3Kg seems to affect primarily chemotaxis of different immune cells induced by various mediators and chemokines (Martin AL, JI 180, 2008; Thomas MS, J Leukoc Biol 84, 2008; Jarmin SJ, JCI 2008; Matthew T, Immunology 126, 2008), as well as degranulation and oxidative burst 45 of innate immuce cells induced by GPCR mediated stimuli such as fMLP, IL-8 or C5a (Condliffe AM, Blood 106, 2005; Yum HK, JI 167, 2001; Pinho V, JI 179, 2007 [0008] The above mentioned findings suggest that selective PI3Kd or dual PI3Kd/PI3Kg pharmacological inhibition represents a promising approach for treating a variety of diseases such as respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis), allergic diseases (allergic 50 rhinitis), inflammatory or autoimmune diseases (rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, myastenia gravias, acute disseminated encephalomyelitis, idiopathic thromocytopenic purpura, Sjoegren’s syndrome, autoimmune hemolytic anemia, type I diabetes, psoriasis, acrodermatitis, angiodermatitis, atopic dermatitis, contact dermatitis, eczema, acne, chronic urticaria, blistering diseases including but not limited to bullous pemphigoid, scleroderma, dermatomyositis, etc.), cardiovascular diseases; 55 viral infection; metabolism/endocrine function disorders; neurological disorders and pain (such as pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, inflammatory neuropathic pain, trigeminal neuralgia or central pain) as well as in bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors (such

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as pancreatic cancer; bladder cancer; colorectal cancer; breast cancer; prostate cancer; renal cancer; hepatocellular cancer; lung cancer; ovarian cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer; non- small cell lung cancer and small- cell lung cancer; melanoma; neuroendocrine cancers; central nervious system cancers; brain tumors; bone cancer; soft tissue sarcoma; chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, T- 5 cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, acute myeloid leukaemia; cutaneous T cell lymphoma, premalignant and malignant skin conditions including but not limited to basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or actinic keratosis (AK)). [0009] There is substantial experimental evidence supporting this view. In rodent models of allergic lung inflammation, genetic or pharmacolocical inactivation of PI3Kd or dual PI3Kd/g dual inhibition reduces cell influx, mucus production, 10 cytokine production and airway hyperreactivity (Nashed et a. 2007, Eur J Immunol 37:416; Lee et al. 2006, FASEB J 20:455 & Lee KS et al. 2006, J Allergy Clin Immunol 118:403; Doukas J, JPET 2009;328:758; Par SJ, ERJ 2010). Moreover, LPS induced lung neutrophil infiltration is blocked by PI3Kd inhibition (Puri KD, Blood 2004;103:3448) and inflammation in response to LPS or tobacco smoke exposure is suppressed by a dual PI3Kd/g inhibitor (Doukas J, JPET 2009;328:758). Moreover, PI3Kd seems to be involved in the reduction of responsiveness to corticosteroid treatment 15 associated with oxidative stress and chronic obstructive pulmonary disease (COPD). This notion is based on the findings that tobacco smoke induced inflammation remains responsive to treatment with budesonide, whereas wild type or PI3Kg deficient mice develop resistance to corticosteroid treatment (Marwick JA, JRCCM 179:542-548, 2009). Similar results were obtained with a PI3Kd selective inhibitor (To Y, AJRCCM 182:897-904, 2010). In addition, in vitro induction of corticosteroid resistance by oxidative stress is prevented by PI3Kd inhibition (To Y, AJRCCM 2010). In COPD patients, 20 lung macrophages display increased expression of PI3Kd and phosphorylation of its downstream effector Akt and non- selective PI3K or PI3Kd- selective inhibition restored the impaired inhibitory efficacy of dexamethasone in PBMC from COPD patients (To Y, AJRCCM 182:897-904, 2010; Marwick JA, JACI 125:1146-53, 2010). [0010] Furthermore, PI3Kd inhibition was effective in a model of contact hypersensitivity (Soond DR, Blood Jan 2010). In a model of experimental autoimmune encephalomyelitis, PI3Kd deficiency or pharmacological inhibition of PI3Kd 25 attenuated T cell activation and function and reduced T cell numbers in the CNS, suggesting a therapeutic benefit of PI3Kd inhibitor in multiple sclerosis and other Th17-mediated autoimmune diseases (Haylock-Jacobs S, J. Autoimmun 2010). In line with that, genetic deficiency or pharmacological inhibition of PI3Kd diminished joint erosion in a mouse model of inflammatory arthritis (Randis TM, Eur J Immunol 38, 2008). Concerning metabolic diseases, PI3Kd overex- pression seems to contribute to excessive vascular contraction and PI3Kd inhibition normalized vascular contractive 30 responses in a mouse model of type I diabetes, suggesting a therapeutic potential of PI3Kd blockade to treat vascular dysfunction in diabetic patients (Pinho JF, Br. J. Pharmacol 161, 2010). [0011] There is also substantial experimental evidence supporting that genetic of pharmacolocical inactivation of PI3Kd or dual PI3Kd/g dual inhibition is effective in the treatment of cancers including but not restricted to leukemias, such as chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukaemia, non-hodgkins 35 lymphoma, B-cell lymphoma, acute myeloid leukaemia, myelo-dysplastic syndrome or myelo-proliferative diseases. In this aspect, the selective PI3Kd inhibitor CAL-1 01 demonstrated anti-proliferative properties on different tumor cells in vitro and efficacy in cancer patients with a dysregulated PI3Kd activity, such as chronic lymphocytic leukemia (Hermann SE, Blood 116:2078-88, 2010; Lannutti BJ, Blood Oct. 2010). [0012] Conditions in which targeting of the PI3K pathway or modulation of the PI3 Kinases, particularly PI3Kd or 40 PI3Kd/g, are contemplated to be therapeutically useful for the treatment or prevention of diseases including: respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis), allergic diseases (allergic rhinitis), inflammatory or autoimmune- mediated diseases (rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, myastenia gravias, acute disseminated encephalomyelitis, idiopathic thromocytopenic purpura, Sjoegren’s syndrome, autoimmune 45 hemolytic anemia, type I diabetes, psoriasis, acrodermatitis, angiodermatitis, atopic dermatitis, contact dermatitis, eczema, acne, chronic urticaria, scleroderma, dermatomyositis and blistering diseases including but not limited to bullous pemphigoid), cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain (such as pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, inflammatory neuropathic pain, trigeminal neuralgia or central pain) as well as in bone marrow and organ transplant 50 rejection; myelo-dysplastic syndrome;myeloproliferative disorders(MPDs); cancer andhematologic malignancies,leukemia, lymphomas and solid tumors (such as pancreatic cancer; bladder cancer; colorectal cancer; breast cancer; prostate cancer; renal cancer; hepatocellular cancer; lung cancer; ovarian cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer; non-small cell lung cancer and small-cell lung cancer; melanoma; neuroendocrine cancers; central nervious system cancers; brain tumors; bone cancer; soft tissue sarcoma; chronic lymphocytic leukemia, 55 B-cell acute lymphoblastic leukemia, T- cell acute lymphoblastic leukaemia, non- hodgkins lymphoma, B-cell lymphoma, acute myeloid leukaemia; cutaneous T cell lymphoma, premalignant and malignant skin conditions including but not limited to basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or actinic keratosis (AK)). [0013] In view of the numerous conditions that are contemplated to benefit by treatment involving modulation of the

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PI3K pathway or modulation of the PI3 Kinases it is immediately apparent that new compounds that modulate PI3K pathways and use of these compounds should provide substantial therapeutic benefits to a wide variety of patients. [0014] Provided herein are novel pyrrolotriazinone derivatives for use in the treatment of conditions in which targeting of the PI3K pathway or inhibition of PI3 Kinases can be therapeutically useful. 5 [0015] The compounds described in the present invention are potent PI3K inhibitors, particularly PI3Kd or dual PK3Kd/g inhibitors. This property makes them useful for the treatment or prevention of pathological conditions or diseases such as respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis), allergic diseases (allergic rhinitis), inflammatory or autoimmune diseases (rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, myas- 10 tenia gravias, acute disseminated encephalomyelitis, idiopathic thromocytopenic purpura, Sjoegren’s syndrome, autoimmune hemolytic anemia, type I diabetes, psoriasis, acrodermatitis, angiodermatitis, atopic dermatitis, contact dermatitis, eczema, acne, chronic urticaria, scleroderma, dermatomyositis and blistering diseases including but not limited to bullous pemphigoid), cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain (such as pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory 15 pain, inflammatory neuropathic pain, trigeminal neuralgia or central pain) as well as in bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (such as polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors (such as pancreatic cancer; bladder cancer; colorectal cancer; breast cancer; prostate cancer; renal cancer; hepatocellular cancer; lung cancer; ovarian cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer; non- small cell 20 lung cancer and small-cell lung cancer; melanoma; neuroendocrine cancers; central nervious system cancers; brain tumors; bone cancer; soft tissue sarcoma; chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, acute myeloid leukaemia; cutaneous T cell lymphoma, premalignant and malignant skin conditions including but not limited to basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or actinic keratosis (AK)). 25 [0016] The compounds described in the present invention are particularly useful for the treatment or prevention of pathological conditions or diseases such as neoplastic diseases (e.g. leukemia, lymphomas, solid tumors); transplant rejection, bone marrow transplant applications (e.g., graft- versus- host disease); autoimmune diseases (e.g. rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes); respiratory inflammation diseases (e.g. asthma, chronic obstructive 30 pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis); skin inflammatory diseases (e.g., atopic dermatitis, contact dermatitis, eczema or psoriasis); premalignant and malignant skin conditions (e.g. basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or actinic keratosis (AK)); neurological disorders and pain (such as pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, inflammatory neuropathic pain, trigeminal neuralgia or central pain) 35 [0017] The compounds described in the present invention are particularly useful for the treatment or prevention of pathological conditions or diseases selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, sq- 40 uamous cell carcinoma and actinic keratosis. [0018] It has now been found that certain pyrrolotriazinone derivatives are novel and potent PI3K inhibitors and can therefore be used in the treatment or prevention of these diseases. [0019] Thus the present invention is directed to compounds of formula (I), or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof: 45

50

55

4 EP 2 518 070 A1

5

10

15

wherein,

X represents a nitrogen atom or a -CR6 group; 20

Ra and Rb each independently represent a hydrogen atom, a C 1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group;

n represents 0, 1, 2 or 3; 25

R1 represents a linear or branched C1-C4 alkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-C14 aryl group, a 5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 14- membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom selected from O, S and N, 30 wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxy group, a cyano group, a linear or branched C 1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)1-3CN group, a -(CH2)0-3OR8 group, a -(CH2)0-3NR7R8 group, a -C(O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R8 group, a -C (O)-(CH2)0-3-NR7R8 group, a -S(O)2(CH2)0-3R8 group or a -S(O)2(CH2)0-3NR7R8 group; 35

R2 and R3 each independently represent a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a C1-C4 alkoxy group, a C 1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group, a C 3-C7 cycloalkyl group, a -NR’R" group, or a linear or branched C 1-C6 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C7 cycloalkyl group; 40

R4 represents a hydrogen atom, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH2)1-4NR’R" group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a 1C-C4 alkoxy group, a cyano group, a C3-C4 cycloalkyl group, a -C(O)-(CH2)0-3-R group or a -C(O)-(CH2)0-3-NR’R" group; 45

R6 represents a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH2)0-3NR’R" group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; 50

R7 and R8 each independently represent a hydrogen atom, a C 1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group;

55 R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C1-C4 alkoxy group or a linear or branched C1-C4 alkyl group;

R5 represents a group selected from:

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i) a group of formula (IIa)

5

10

15 ii) a group of formula (IIb)

20

25

and

iii) a group of formula (IIc) 30

35

wherein

40 Y represents a linker selected from a -NR’- group, -O- or -S-; wherein R’ is as defined above;

(*) represents where R5 is bonded to the carbon atom attached to R4 and to the pyrrolotriazinone group;

W1 represents a -CR11 group and W2 represents a nitrogen atom, or W1 represents a nitrogen atom and 45 W2 represents a -CR12 group;

G1 represents a -CR 14 group and G 2 represents a nitrogen atom, or G 1 represents a nitrogen atom and G 2 represents a -CR15 group, or G1 represents a -CR14 group and G2 represents a -CR15 group;

50 G3 represents a nitrogen atom or a -CR16 group;

R9, R10, R11, R12, R13, R14, R15 and R16 each independently represent a hydrogen atom, a C1-C4 alkoxy group, a C 1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group, a C 3-C4 cycloalkyl group, a -(CH 2)0-3CN group, a -C(O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C(O)-(CH2)0-3-NR’R", a -(CH2)0-3NR’R" group, 55 or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" are as defined above;

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R17 represents a group selected from

a) a group of formula (IIIa),

5

10

15

b) a group of formula (IIIb),

20

25

30 c) a group of formula (IIIc), and

35

40

45 d) a group of formula (IIId),

50

55

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5

10

wherein 15

G4 represents a nitrogen atom or a -CR22 group; G5 and G6 each independently represents a nitrogen atom or a -carbon atom, wherein when one of G 5 and G6 represents a nitrogen atom the remaining represents a carbon atom; G7 represents a -NH group or a -CH group; 20 G8 represents a nitrogen atom or a -CR23 group; G9 represents a nitrogen atom or a -CR24 group; G10 represents a nitrogen atom or a -CR25 group; G11 represents a nitrogen atom or a -CR26 group; G12 represents a nitrogen atom or a -CR27 group; 25 G13 represents a nitrogen atom or a -CR28 group; G14 and G15 each independently represents a nitrogen atom or a carbon atom, wherein when one of G14 and G15 represents a nitrogen atom the remaining represents a carbon atom; G16 represents a -NH group or a -CH group; G17 represents a nitrogen atom or a -CR29 group; 30 G18 represents a nitrogen atom or a -CR30 group; R18, R 19, R 20, R 21, R 22, R23, R 24, R 25, R26, R27, R28, R29, and R 30 each independently represent a hydrogen atom, a C 1-C4 alkoxy group, a C 1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group, a C 3-C4 cycloalkyl group, a -(CH2)0-3CN group, a -C(O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C(O)-(CH2)0-3-NR’R", a -(CH2)0-3NR’R" group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or 35 substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" are as defined above; and wherein Y is as defined above;

or in the case that Y represents a -NR’- group, R 4 together with the -NR’- group and the carbon atom to which both R4 and the -NR’- group are bonded form a 4- to 7-membered, saturated N-containing heterocyclyl group, which 40 heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group.

[0020] The dotted line in the group of formula (IIIa)

45

50

55

denotes that there are two double bounds in the C5 heteroaryl ring, whose position may vary depending on which G5, G6, G7, G8 or G9 represents a nitrogen atom or a carbon atom.

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[0021] The invention further provides synthetic processes and intermediates described herein, which are useful for preparing said compounds. [0022] The invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy. 5 [0023] The invention also provides a pharmaceutical composition comprising the compounds of the invention and a pharmaceutically-acceptable diluent or carrier. [0024] The invention is also directed to the compounds of the invention as described herein, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; 10 inflammatory or autoimmune- mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/ endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid artritis (RA), multiple sclerosis (MS), amyotrophic lateral sclerosis, 15 Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and actinic keratosis (AK). [0025] The invention is also directed to use of the compounds of the invention as described herein, in the manufacture 20 of a medicament for treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phos- phoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); 25 cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particularwherein thepathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid artritis (RA), multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell car- 30 cinoma (BCC), squamous cell carcinoma (SCC) and actinic keratosis (AK). [0026] The invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; 35 neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid artritis (RA), multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), 40 cystic fibrosis (CF), idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and actinic keratosis (AK). [0027] The invention also provides a combination product comprising (i) the compounds of the invention as described herein; and (ii) one or more additional active substances which are known to be useful in the treatment of respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological dis- 45 orders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particularwherein thepathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid artritis (RA), multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemo- 50 lytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and actinic keratosis (AK). [0028] As used herein the term C 1-C6 alkyl embraces linear or branched radicals having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n- propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 55 2-methylbutyl, isopentyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1- dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2- dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl and iso-hexyl radicals. [0029] When it is mentioned that the alkyl radical may be optionally substituted it is meant to include linear or branched

9 EP 2 518 070 A1

alkyl radical as defined above, which may be unsubstituted or substituted in any position by one or more substituents, for example by 1, 2 or 3 substituents. When two or more substituents are present, each substituent may be the same or different. [0030] As used herein, the term C1-C4 haloalkyl group is an alkyl group, for example a C1-C4 or C1-C2 alkyl group, 5 which is bonded to one or more, preferably 1, 2 or 3 halogen atoms. Preferably, said haloakyl group is chosen from -CCl3, -CHF2 and -CF3. [0031] As used herein, the term C1-C4 hydroxyalkyl embraces linear or branched alkyl radicals having 1 to 4 carbon atoms, any one of which may be substituted by one or more, preferably 1 or 2, more preferably 1 hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl. 10 [0032] As used herein, the term C1-C4 alkoxy (or alkyloxy) embraces linear or branched oxycontaining radicals each having alkyl portions of 1 to 4 carbon atoms. [0033] As used herein, the term C3-C10 cycloalkyl embraces saturated monocyclic or polycyclic carbocyclic radicals having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms. An optionally substituted3 -CC 10 cycloalkyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. When a 15 C3-C10 cycloalkyl radical carries 2 or more substituents, the substituents may be the same or different. Typically the substituents on a C3-C10 cycloalkyl group are themselves unsubstituted. Polycyclic cycloalkyl radicals contains two or more fused cycloalkyl groups, preferably two cycloalkyl groups. Typically, polycyclic cycloalkyl radicals are selected from decahydronaphthyl (decalyl), bicyclo[2.2.2]octyl, adamantly, camphyl or bornyl groups. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooc- 20 tyl, cyclononyl and cyclodecyl. [0034] As used herein, the term C 3-C10 cycloalkenyl embraces partially unsaturated carbocyclic radicals having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms. A C3-C10 cycloalkenyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. When a C3-C10 cycloalkenyl radical carries 2 or more substituents, the substituents may be the same or different. Typically, the substituents on a cycloalkenyl group 25 are themselves unsubstituted. Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl and cyclodece- nyl. [0035] As used herein, the term C 6-C14 aryl radical embraces typically a C6-C14, more preferably C6-C10 monocyclic or bicyclic aryl radical such as phenyl, naphthyl, anthranyl and phenanthryl. Phenyl is preferred. A said optionally sub- 30 stituted C6-C14 aryl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. When a C6-C14 aryl radical carries 2 or more substituents, the substituents may be the same or different. Unless otherwise specified, the substituents on a C6-C14 aryl group are typically themselves unsubstituted. [0036] As used herein, the term 5- to 14- membered heteroaryl radical embraces typically a 5-to 14- membered ring system, preferably a 5- to 10- membered ring system, more preferably a 5- to 6- membered ring system, comprising at 35 least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N. A 5- to 14-membered heteroaryl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom. [0037] A said optionally substituted 5- to 14- membered heteroaryl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. When a 5- to 14- membered heteroaryl radical carries 2 or more substituents, the substituents may be the same or different. Unless otherwise specified, the substituents on a 5- 40 to 14- membered heteroaryl radical are typically themselves unsubstituted. [0038] Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxa- zolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, in- dolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2H- pyrazolo[3,4-d]pyrimidinyl, 45 1 H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d] pyrimidinyl and the various pyrrolopyridyl radicals. [0039] As used herein, the term 5- to 14- membered heterocyclyl radical embraces typically a non- aromatic, saturated or unsaturated C5-C14 carbocyclic ring system, preferably C5-C10 carbocyclic ring system, more preferably C5-C6 carbocyclic ring system, in which one or more, for example 1, 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S. A heterocyclyl radical may be a single ring or two fused 50 rings wherein at least one ring contains a heteroatom. When a 5 to 14- membered heterocyclyl radical carries 2 or more substituents, the substituents may be the same or different. [0040] A said optionally substituted 5- to 14- membered heterocyclyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. Typically, the substituents on a 5 to 14- membered heterocyclyl radical are themselves unsubstituted. 55 [0041] Examples of 5- to 14-membered heterocyclyl radicals include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, quinuclidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, imidazolyl, oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, 4,5-dihydro-oxazolyl, 2-benzofuran-1 (3H)-one, 1,3-dioxol-2-one, tetrahydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothi-

10 EP 2 518 070 A1

opyranyl, 1,4-azathianyl, oxepanyl, thiephanyl, azepanyl, 1,4-dioxepnayl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithi- epanyl, 1,4-thiezepanyl, 1,4-diazepanyl, tropanyl, (1S,5R)-3-aza-bicyclo[3.1.0]hexyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 2,3-hydrobenzofuranyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, isoindolinyl and indolinyl. 5 [0042] Where a 5- to 14-membered heterocyclyl radical carries 2 or more substituents, the substituents may be the same or different. [0043] As used herein, the bicyclic N- containing heteroaryl group is a C 8-C10 membered ring system where two rings have been fused and wherein at least in one ring one of the carbon atoms is replaced by N and optionally in which 1, 2, 3, or 4, preferably 1, 2, or 3 further carbon atoms of any ring which form the group are replaced by N. 10 [0044] Examples include indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo [2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolinyl, indazolyl, purinyl, indolinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolyl, isoquinolyl, cinnolinyl, azaquinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, pyrido [3,2-d]pyrimid- 15 inyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, pyrido[2,3-b] pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl and pyrimido[4,5-d]pyrimidinyl. [0045] As used herein, some of the atoms, radicals, moieties, chains and cycles present in the general structures of the invention are "optionally substituted". This means that these atoms, radicals, moieties, chains and cycles can be either unsubstituted or substituted in any position by one or more, for example 1, 2, 3 or 4, substituents, whereby the 20 hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaced by chemically acceptable atoms, radicals, moieties, chains and cycles. When two or more substituents are present, each substituent may be the same or different. The substituents are typically themselves unsubstituted. [0046] As used herein, the term halogen atom embraces chlorine, fluorine, bromine and iodine atoms. A halogen atom is typically a fluorine, chlorine or bromine atom, most preferably chlorine or fluorine. The term halo when used as a prefix 25 has the same meaning. [0047] Compounds containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, in the form of racemic mixtures and in the form of mixtures enriched in one or more stereoisomer. The scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures. 30 [0048] Conventional techniques for the preparation/ isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomehc mixture may be separated by chroma- 35 tography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate 40 affords the enriched mixture. Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds" by Ernest L. Eliel (Wiley, New York, 1994). [0049] Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. Oki (Oki, M; Topics in Stereochemistry 1983, 1) defined atropisomers as conformers that interconvert with a half-life of more than 1000 seconds at a given 45 temperature. The scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual atropisomers (an atropisomer "substantially free" of tis corresponding enantionmer) and stereoisomer-enriched mixtures, i.e. mixtures of atropisomers. [0050] Separation of atropisomers is possibly by chiral resolution methods such as selective crystallization. In an atropo-enantioselective or atroposelective synthesis one atropisomer is formed at the expense of the other. Atropose- 50 lective synthesis may be carried out by use of chiral auxiliaries like a Corey- Bakshi-Shibata (CBS) catalyst (asymmetric catalyst derived from proline) in the total synthesis of knipholone or by approaches based on thermodynamic equilibration when an isomerization reaction favors one atropisomer over the other. [0051] As used herein, the term pharmaceutically acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically- 55 acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids. [0052] Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid; and organic acids, for example citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, meth-

11 EP 2 518 070 A1

anesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic acid, xinafoic (1-hydroxy-2-naphthoic acid), na- padisilic (1,5-naphthalenedisulfonic acid) and the like. Particularly preferred are salts derived from fumaric, hydrobromic, hydrochloric, acetic, sulfuric, methanesulfonic, xinafoic, and tartaric acids. [0053] Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, cop- 5 per, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. [0054] Salts derived from pharmaceutically- acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N, N’-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 10 2-dimethylaminoethanol, ethanolamine, ethylenediamine, ethylmorpholine, N- N-ethylpiperidine, glucamine, glu- cosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. [0055] Other preferred salts according to the invention are quaternary ammonium compounds wherein an equivalent 15 of an anion (X-) is associated with the positive charge of the N atom. X - may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate. X- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, trifluoroacetate 20 or methanesulphonate. [0056] As used herein, an N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent. [0057] The present invention also embraces tautomeric forms of the compounds of formula (I), or pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers or deuterated derivatives thereof. 25 [0058] The compounds of the invention may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules. The term hydrate is employed when said solvent is water. Examples of solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mix- 30 tures thereof. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate. [0059] Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate. Additionally, it is specifically contemplated that in the present invention less than one solvent molecule may be associated with one 35 molecule of the compounds of the present invention, such as a hemihydrate. Furthermore, solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non-solvate form of the compounds. [0060] The invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic 40 mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive 45 isotopes tritium, 3H, and carbon-14, 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor 50 occupancy. [0061] Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. [0062] Preferred isotopically-labeled compounds include deuterated derivatives of the compounds of the invention. 55 As used herein, the term deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Deuterium (D or 2H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %. [0063] Hydrogen deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded

12 EP 2 518 070 A1

hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial. [0064] Typically, a deuterated derivative of a compound of the invention has an isotopic enrichment factor (ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium present at a site designated 5 as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation). [0065] In a preferred embodiment, the isotopic enrichment factor is at least 5000 (75% deuterium). In a more preferred embodiment, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In a most preferred embodiment, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent from 10 the other deuteration sites. [0066] The isotopic enrichment factor can be determined using conventional analytical methods known too en ordinary skilled in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR). [0067] Prodrugs of the compounds described herein are also within the scope of the invention. Thus certain derivatives of the compounds of the present invention, which derivatives may have little or no pharmacological activity themselves, 15 when administered into or onto the body may be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as ’prodrugs’. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharma- ceutical Association). 20 [0068] Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the present invention with certain moieties known to those skilled in the art as ’pro- moieties’ as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985). [0069] In the case of compounds that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystalline or polymorphic forms, or in an amorphous form, all of which are intended to 25 be within the scope of the present invention. [0070] As used herein, the term PI3Kd inhibitor generally refers to a compound that inhibits the activity of the PI3Kd isoform more effectively than other isoforms of the PI3K family. [0071] As used herein, the term PI3Kd/g inhibitor generally refers to a compound that inhibits the activity of both the PI3Kd isoform and the PI3Kd isoform more effectively than other isoforms of the PI3K family. 30 [0072] The relative efficacies of compounds as inhibitors of an enzyme activity (or other biological activity) can be established by determining the concentrations at which each compound inhibits the activity to a predefined extent and then comparing the results. Typically, the preferred determination is the concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or "IC 50." IC50 determinations can be accomplished using conventional techniques known in the art. In general, an IC50 can be determined by measuring the activity of a given 35 enzyme in the presence of a range of concentrations of the inhibitor under study. The experimentally obtained values of enzyme activity then are plotted against the inhibitor concentrations used. The concentration of the inhibitor that shows 50% enzyme activity (as compared to the activity in the absence of any inhibitor) is taken as the IC50 value. [0073] Accordingly, a PI3Kd inhibitor alternatively can be understood to refer to a compound that exhibits a 50% inhibitory concentration (IC50) with respect to PI3Kd that is at least of less than about 100 PM, preferably of less than 40 about 50 PM, more preferably of less than about 20 PM, even more preferably of less than about 10 PM PI3K HTRF assay (as described in Gray et al. Anal Biochem, 2003; 313: 234-45) [0074] Typically, in the compound of formula (I), X represents a nitrogen atom or a -CR6 group. [0075] Typically, in the compound of formula (I), R a and R b each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group. 45 [0076] Preferably, Ra and Rb each independently represent a hydrogen atom, a methyl group or an ethyl group. [0077] Typically, n represents 0, 1 or 2, preferably 0 or 1, more preferably 0. [0078] Typically, in the compound of formula (I) R 1 represents a C 1-C3 alkyl group, a C 3-C7 cycloalkyl group, a phenyl group, a naphtyl group, a 5- to 10- membered monocyclic or bicyclic heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, or a 5- to 10- membered monocyclic or bicyclic heterocyclyl group containing 50 containing one, two or three heteroatoms selected from O, S and N; wherein the cycloalkyl, phenyl, naphtyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxy group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3OR8 group, a -(CH2)0-3NR7R8 group, a -C(O)-(CH2)0-3-R8 group or a -C (O)-(CH2)0-3-NR7R8 group; wherein R7 and R8 are as defined above. 55 [0079] Preferably, R1 represents a C 3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered monocyclic or bicyclic heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group or a morpholinyl group; wherein the cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl or morpholinyl groups are unsubstituted or substituted

13 EP 2 518 070 A1

by one or more substituents selected from a halogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3OR8 group, a -(CH2)0-3NR7R8 group, a -C (O)-(CH2)0-3-R8 group or a -C(O)-(CH2)0-3-NR7R8 group; wherein R7 and R8 each independently represent a hydrogen atom or a C1-C4 alkyl group 5 [0080] More preferably R1 represents a phenyl group or a pyridinyl group, which phenyl or pyridinyl is unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a linear or branched C1-C3 alkyl group or a -(CH2)0-3OCH3 group. [0081] Preferably, when R 1 represents a phenyl group or a pyridinyl group, said phenyl and pyridinyl groups are directly bonded to the pyrrolotriazinone group. In other words, the linker -(Ra-C-Rb)0-3- is not present. More preferably, R1 10 represents a phenyl group. [0082] Preferably, when R1 is a phenyl group, it is unsubstituted or substituted by one, two or three substituents selected from a halogen atom (preferably a fluorine atom or a chlorine atom), a linear or branched C1-C3 alkyl group (preferably a methyl group), or a -OCH3 group. [0083] Preferably, when R1 is a pyridinyl or pyperidinyl group, said groups are linked to the rest of the molecule via a 15 ring carbon atom, in other words they are linked to the pyrrolotriazinone group via a ring carbon atom. Substituents on a pyridinyl group may be present on any ring atom but are preferably present on a carbon atom. Substituents on a piperidinyl group may be present on any ring atom but are preferably present on the nitrogen atom. [0084] Typically, in the compound of formula (I) R2 represents a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a 20 -(CH2)0-3NR’R" group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C3 alkoxy group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, or a linear or branched C1-C3 alkyl group. [0085] Preferably R2 represents a hydrogen atom, a halogen atom, a hydroxy group, a C1-C3 alkoxy group, a C1-C3 haloalkyl group, a C3-C4 cycloalkyl group, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched 25 C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group. [0086] More preferably R2 represents a hydrogen atom, a halogen atom, -NH 2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C3 alkyl group. Most preferably R2 represents a hydrogen atom or a methyl group. [0087] Typically, in the compound of formula (I) R3 represents a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a 30 -(CH2)0-3NR’R" group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C3 alkoxy group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, or a linear or branched C1-C3 alkyl group. [0088] Preferably, in the compound of formula (I) R3 represents a hydrogen atom, a halogen atom, a hydroxy group, a C1-C3 alkoxy group, a C1-C3 haloalkyl group, a C 3-C4 cycloalkyl group, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 35 group, or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C 1-C2 alkoxy group [0089] More preferably R3 represents a hydrogen atom, a halogen atom, -NH 2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C3 alkyl group. Most preferably R2 represents a hydrogen atom or a methyl group. [0090] Typically, in the compound of formula (I), R4 represents a R4 represents a hydrogen atom, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)1-4NR’R" group, or a 40 linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C3 alkoxy group, a -C (O)-(CH2)0-3-R’ group or a -C(O)-(CH2)0-3-NR’R" group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, or a linear or branched C1-C3 alkyl group. More preferably, R4 represents a hydrogen atom, a C1-C3 alkoxy group, a C 1-C3 haloalkyl group, a C 3-C4 cycloalkyl group, or a linear or branched C 1-C3 alkyl group. Most preferably R4 represents a hydrogen atom, a C1-C3 haloalkyl group or a linear or branched C1-C3 alkyl group. 45 [0091] Typically, in the compound of formula (I), R6 represents a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3NR’R" group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C3 alkoxy group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, or a linear or branched C1-C3 alkyl group. Preferably, R6 represents a hydrogen atom, a halogen atom, a C1-C3 alkoxy group, a 50 C1-C3 haloalkyl group, a C3-C4 cycloalkyl group, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C 1-C2 alkoxy group. More preferably, R6 represents a hydrogen atom, a halogen atom, a C1-C3 haloalkyl group (preferably a -CHF2 group or a -CF3 group), or a linear or branched C1-C3 alkyl group. [0092] In a particular embodiment, R5 represents a group selected from 55 i) a group of formula (IIa-1), and

14 EP 2 518 070 A1

5

10

ii) a group of formula (IIa-2)

15

20

25

wherein

R9, R10, R11 and R12 each independently represent a hydrogen atom, a C 1-C4 alkoxy group, a C1-C4 haloalkyl 30 group, a C 1-C4 hydroxyalkyl group, a C 3-C4 cycloalkyl group, a -(CH 2)0-3CN group, a -C (O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a1 -CC4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C1-C4 alkoxy group or a linear or branched C1-C4 alkyl group. 35

[0093] In this particular embodiment, preferably R5 represents a group of formula (IIa-2) wherein R9, R10, and R12 each independently represent a hydrogen atom, a -(CH 2)0-3CN group, a -C(O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C(O)-(CH2)0-3-NR’R", a -(CH2)0-3NR’R" group, or a linear or branched C1-C4 alkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C 1-C4 alkoxy group or a linear or branched C 1-C4 40 alkyl group. More preferably, R9 and R12 each independently represent a hydrogen atom and 10 R represents a - (CH2)0-3NR’R" group wherein R’ and R" each independently represent a hydrogen atom or methyl group. Even more preferably, R9 and R12 each independently represent a hydrogen atom and R10 represents a -NH2 group. [0094] In another particular embodiment, R5 represents a group selected from

45 i) a group of formula (IIb-1),

50

55

15 EP 2 518 070 A1

ii) a group of formula (IIb-2),

5

10

15 iii) a group of formula (IIb-3),

20

25

iv) a group of formula (IIb-4), and 30

35

40 v) a group of formula (IIb-5),

45

50

wherein 55

R13, R14, R15 and R16 each independently represent a hydrogen atom, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3CN group, a -C(O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl group,

16 EP 2 518 070 A1

which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C1-C4 alkoxy group or a linear or branched C1-C4 alkyl group; and wherein Y represents a linker selected from a -NR’-group, -O- or -S-; wherein R’ is as defined above; 5

or in the case that Y represents a -NR’- group, R4 together with the -NR’- group and the carbon atom to which both R4 and the -NR’- group are bonded form a 4- to 7- membered, saturated N- containing heterocyclyl group, which heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group. 10 [0095] In this particular embodiment, preferably R5 represents a group selected from a group of formula (IIb-1) and a group of formula (IIb-2) wherein R13, R14, R15 and R 16 each independently represent a hydrogen atom, a -(CH 2)0-3CN group, a -C (O)-(CH2)0-3-NR’R" or a -(CH2)0-3NR’R" group; wherein R’ and R" each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group; and wherein Y represents a -NR’- group, wherein R’ is as defined before. 15 [0096] Preferably, when R5 is a group of formula (IIb-1) R 14 and R16 each independently represent a hydrogen atom, and R13 and R15 each independently represent a hydrogen atom, a -C(O)-(CH2)0-3-NR’R" or a -(CH2)0-3NR’R" group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, or a linear or branched C 1-C3 alkyl group; wherein Y represents a -NR’- group, wherein R’ is as defined before. Even more preferably, R14 and R16 each independently represent a hydrogen atom, and R13 and R15 each independently represent a hydrogen atom, a -C 20 (O)-NR’R’ group or a - NR’R" group; wherein R’ and R" each independently represent a hydrogen atom or a methyl group; wherein Y represents a a -NH- group. [0097] Preferably, when R5 is a group of formula (IIb-2) R13 represents a hydrogen atom, and R14 and R15 each independently represent a hydrogen atom, a -(CH2)0-3CN group, a -C(O)-(CH2)0-3-NR’R" or a -(CH2)0-3NR’R" group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, or a linear or branched C 1-C3 alkyl 25 group; wherein Y represents a -NR’- group, wherein R’ is as defined before. Even more preferably, R13 represents a hydrogen atom, and R14 and R15 each independently represent a hydrogen atom, a -CN group or a -NR’R" group; wherein R’ and R" each independently represent a hydrogen atom or a methyl group; and wherein Y represents a -NH- group. Still more preferably, R 13 represents a hydrogen atom, and R 14 and R 15 each independently represent a hydrogen atom, a -CN group or a -NH2 group. 30 [0098] In a further particular embodiment, R5 represents a group selected from

i) a group of formula (IIIa-1),

35

40

ii) a group of formula (IIIa-2), 45

50

55 iii) a group of formula (IIIa-3),

17 EP 2 518 070 A1

5

10 iv) a group of formula (IIIa-4),

15

20

v) a group of formula (IIIa-5),

25

30

35 vi) a group of formula (IIIa-6),

40

45

vii) a group of formula (IIIa-7),

50

55

18 EP 2 518 070 A1

viii) a group of formula (IIIa-8),

5

10

ix) a group of formula (IIIa-9), 15

20

25 X) a group of formula (IIIa-10),

30

35

xi) a group of formula (IIIa-11), 40

45

50

xii) a group of formula (IIIa-12),

55

19 EP 2 518 070 A1

5

10 xiii) a group of formula (IIIa-13),

15

20

xiv) a group of formula (IIIa-14), 25

30

35 xv) a group of formula (IIIa-15),

40

45

xvi) a group of formula (IIIa-16),

50

55

20 EP 2 518 070 A1

xvii) a group of formula (IIIa-17),

5

10

xviii) a group of formula (IIIa-18),

15

20

25 xix) a group of formula (IIIa-19),

30

35

xx) a group of formula (IIIa-20),

40

45

xxi) a group of formula (IIIa-21), and 50

55

21 EP 2 518 070 A1

5

10 xxii) a group of formula (IIIa-22)

15

20

wherein

25 R18, R22, R23, and R24 each independently represent a hydrogen atom, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3CN group, a -C(O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" each independently represent a hydrogen atom, a 30 hydroxy group, a C1-C4 alkoxy group or a linear or branched C1-C4 alkyl group; and wherein Y represents a linker selected from a -NR’-group, -O- or -S-; wherein R’ is as defined above;

or in the case that Y represents a -NR’- group, R4 together with the -NR’- group and the carbon atom to which both R4 and the -NR’- group are bonded form a 4- to 7- membered, saturated N- containing heterocyclyl group, which heterocyclyl 35 group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group. [0099] In this particular embodiment, preferably R5 represents a group of formula (IIIa-1) wherein

R18 and R23 each independently represent a hydrogen atom, a -(CH2)0-3CN group, a -C(O)-(CH2)1-3-CN group, a 40 -C(O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a 1C-C4 alkoxy group or a linear or branched C1-C4 alkyl group; and wherein Y is as defined above;

or in the case that Y represents a -NR’- group, R4 together with the -NR’- group and the carbon atom to which both R4 45 and the -NR’- group are bonded form a 4- to 7- membered, saturated N- containing heterocyclyl group, which heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group. [0100] Preferably, when R5 is a group of formula (IIIa- 1) R18 and R23 each independently represent a hydrogen atom, a -C(O)-(CH2)0-3-NR’R" or a -(CH2)0-3NR’R" group; wherein R’ and R" each independently represent a hydrogen atom, 50 a hydroxy group, or a linear or branched C 1-C3 alkyl group; wherein Y represents a -NR’- group or -S-, wherein R’ is as defined before. Even more preferably, R18 and R23 each independently represent a hydrogen atom or a -NR’R" group; wherein R’ and R" each independently represent a hydrogen atom or a methyl group; wherein Y represents a -NR’- group or -S-, wherein R’ is as defined before. [0101] Preferably, when R5 is a group of formula (IIIa-1) wherein Y represents a -NR’- group, wherein R’ is a linear 55 or branched C1-C4 alkyl group; R4 together with the -NR’- group and the carbon atom to which both R4 and the -NR’- group are bonded form a 4- to 7-membered, saturated N-containing heterocyclyl group, which heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group. More preferably, R4 together with the -NR’- group of R5 and the carbon atom to which

22 EP 2 518 070 A1

both R4 and the - NR’-group are bonded form an azetidinyl group, a pyrrolidinyl group, a piperidinyl group or a piperazinyl group; even more preferably a pyrrolidinyl group or a piperidinyl group. [0102] In another particular embodiment, R5 represents a group selected from

5 i) a group of formula (IIIb-1),

10

15

ii) a group of formula (IIIb-2),

20

25

30 iii) a group of formula (IIIb-3),

35

40

iv) a group of formula (IIIb-4),

45

50

55 v) a group of formula (IIIb-5),

23 EP 2 518 070 A1

5

10

vi) a group of formula (IIIb-6),

15

20

25 vii) a group of formula (IIIb-7), and

30

35

viii) a group of formula (IIIb-8),

40

45

50 wherein

R18, R22, R25, R26, and R 27 each independently represent a hydrogen atom, a C 1-C4 alkoxy group, a C 1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3CN group, a -C(O)-(CH2)1-3-CN group, a 55 -C(O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C1-C4 alkoxy group or a linear or branched C1-C4 alkyl group; and wherein Y represents a linker

24 EP 2 518 070 A1

selected from a -NR’-group, -O- or -S-; wherein R’ is as defined above;

or in the case that Y represents a -NR’- group, R4 together with the -NR’- group and the carbon atom to which both R4 and the -NR’- group are bonded form a 4- to 7- membered, saturated N- containing heterocyclyl group, which heterocyclyl 5 group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group. [0103] In a further particular embodiment, R5 represents a group selected from

i) a group of formula (IIIc-1), and 10

15

20

ii) a group of formula (IIIc-2),

25

30

35 wherein

R19, R20, and R28 each independently represent a hydrogen atom, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3CN group, a -C(O)-(CH2)1-3-CN group, a -C (O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl group, 40 which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C1-C4 alkoxy group or a linear or branched C1-C4 alkyl group; and wherein Y represents a linker selected from a -NR’-group, -O- or -S-; wherein R’ is as defined above;

45 or in the case that Y represents a -NR’- group, R4 together with the -NR’- group and the carbon atom to which both R4 and the -NR’- group are bonded form a 4- to 7- membered, saturated N- containing heterocyclyl group, which heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group. [0104] In another particular embodiment, R5 represents a group selected from 50 i) a group of formula (IIId-1),

55

25 EP 2 518 070 A1

5

10

ii) a group of formula (IIId-2), and

15

20

25 iii) a group of formula (IIId-3),

30

35

wherein

40 R21, R28, R29, and R30 each independently represent a hydrogen atom, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3CN group, a -C(O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" each independently represent a hydrogen atom, a 45 hydroxy group, C1-C4 alkoxy group or a linear or branched C1-C4 alkyl group; and wherein Y represents a linker selected from a -NR’- group, - O- or -S-; wherein R’ is as defined above;

or in the case that Y represents a -NR’- group, R4 together with the -NR’- group and the carbon atom to which both R4 and the -NR’- group are bonded form a 4- to 7- membered, saturated N- containing heterocyclyl group, which heterocyclyl 50 group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group. [0105] Typically, in the compound of formula (I), Y represents a linker selected from a -NR’- group, -O- or -S-; wherein R’ represents a hydrogen atom, a hydroxy group, a 1C-C4 alkoxy group or a linear or branched 1C-C4 alkyl group. Preferably Y represents a linker selected from a -NR’- group or -S-; wherein R’ represents a hydrogen atom, a hydroxy 55 group, a C1-C4 alkoxy group or a linear or branched C1-C4 alkyl group. More preferably Y represents a linker selected from a -NR’- group or -S-; wherein R’ represents a hydrogen atom or a linear or branched1 -CC3 alkyl group. Most preferably Y represents a -NR’- group; wherein R’ represents a hydrogen atom or a linear or branched C 1-C3 alkyl group. [0106] When R’ and/or R" are attached to a nitrogen atom, preferably R’ and/or R" do not represent a hydroxy group

26 EP 2 518 070 A1

or alkoxy group. [0107] Where any of the above moieties represent -C (O)-(CH2)0-3-R8 or -C(O)-(CH2)0-3-R’, it is preferable that R 8 and R’ do not represent a hydrogen atom if the alkylene spacer moiety is absent. [0108] Preferably in the compound of formula (I): 5

Ra and Rb each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group;

n represents 0, 1 or 2;

10 R1 represents a linear or branched C 1-C4 alkyl group, a C 3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered monocyclic or bicyclic heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group or a morpholinyl group; wherein the cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl or morpholinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or 15 branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3OR8 group, a -(CH 2)0-3NR7R8 group, a -C (O)-(CH2)0-3-R8 group or a -C (O)-(CH2)0-3-NR7R8 group; wherein R7 and R8 each independently represent a hydrogen atom or a C1-C4 alkyl group;

R2 represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-C3 alkoxy group, a C 1-C3 haloalkyl group, 20 a C3-C4 cycloalkyl group, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group;

R3 represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-C3 alkoxy group, a C 1-C3 haloalkyl group, a C3-C4 cycloalkyl group, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl 25 group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group;

R4 represents a hydrogen atom, a C 1-C3 alkoxy group, a C 1-C3 haloalkyl group, a C 3-C4 cycloalkyl group, or a linear or branched C1-C3 alkyl group;

30 R6 represents a hydrogen atom, a halogen atom, a C 1-C3 alkoxy group, a C 1-C3 haloalkyl group, a C 3-C4 cycloalkyl group, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group;

R5 represents a moiety of formula (II-a2), (IIb-1), (IIb-2) or (IIIa-1): 35

40

45

wherein:

50 $ R9, R10, and R12 each independently represent a hydrogen atom, a -(CH 2)0-3CN group, a -C(O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C(O)-(CH2)0-3-NR’R", a -(CH2)0-3NR’R" group, or a linear or branched C1-C4 alkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C 1-C4 alkoxy group or a linear or branched C1-C4 alkyl group; $ R13, R14, R15 and R16 each independently represent a hydrogen atom, a 2 -(CH)0-3CN group, a -C 55 (O)-(CH2)0-3-NR’R" or a -(CH2)0-3NR’R" group; wherein R’ and R" each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group; $ R18 and R23 each independently represent a hydrogen atom, a -(CH2)0-3CN group, a -C(O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C(O)-(CH2)0-3-NR’R", a -(CH2)0-3NR’R" group, or a linear or branched

27 EP 2 518 070 A1

C1-C4 alkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C 1-C4 alkoxy group or a linear or branched C1-C4 alkyl group; $ Y represents a -NR’- group, -O- or -S-; wherein R’ represents hydrogen or a linear or branched C1-C4 alkyl group; or in the case that Y represents a -NR’-group, R4 together with the -NR’- group and the carbon atom to 5 which both R4 and the -NR’- group are bonded form a 4- to 7- membered, saturated N- containing heterocyclyl group.

[0109] In a particularly preferred embodiment, in the compound of formula (I)

10 X represents a nitrogen atom or a -CR6 group;

Ra and Rb each independently represent a hydrogen atom or a methyl group;

n represents 0 or 1; 15

R1 represents a methyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridinyl group, a piperidinyl group or a tetrahydropyranyl group; wherein the cycloalkyl, phenyl, pyridinyl, piperidinyl or tetrahydropyranyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C 1-C3 alkyl group, a -NR 7R8 group or 20 a -OR8 group; wherein R7 and R8 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group;

R2 and R3 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group;

25 R4 represents a hydrogen atom, a C1-C3 haloalkyl group, or a linear or branched C1-C3 alkyl group;

R6 represents a hydrogen atom, a halogen atom, a C1-C3 haloalkyl group,a linear or branched C1-C3 alkyl group or a cyclopropyl group;

30 R5 represents a group selected from:

i) a group of formula (IIa), which group is a purinyl group unsubstituted or substituted by a -NR’R" group; ii) a group of formula (IIb), which group is selected from a -NH-pyridinyl group, a -S-pyridinyl group, a -NH- pyrimidinyl group or a -S-pyrimidinyl group and preferably from a -NH-pyridinyl group and a -NH-pyrimidinyl 35 group; wherein the pyridinyl or pyrimidinyl groups are unsubstituted or substituted by one, two or three substituents selected from a -(CH2)0-3CN group, a -C(O)-(CH2)0-3-NR’R" or a -(CH2)0-3NR’R" group and preferably from a -CN group, a -C(O)NH2 or a -NH2 group; and iii) a group of formula (IIc), which group is selected from a -NH- purinyl group or a -S-purinyl group; wherein the purinyl group is unsubstituted or substituted by a -(CH2)0-3NR’R" group; or 40

R4 and R5 together with the carbon atom to which they are attached form a pyrrolidinyl-purinyl group, wherein the purinyl group is unsubstituted or substituted by a -(CH 2)0-3NR’R" group;

R’ and R" each independently represent a hydrogen atom, a C 1-C3 alkoxy group or a linear or branched C 1-C3 alkyl 45 group, preferably a a hydrogen atom or a linear or branched C1-C3 alkyl group.

[0110] In another particularly preferred emobodiment, in the compound of formula (I)

X represents a nitrogen atom or a -CR6 group; 50

Ra and Rb each independently represent a hydrogen atom or a methyl group;

n represents 0 or 1;

55 R1 represents a methyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridinyl group, a piperidinyl group or a tetrahydropyranyl group; wherein the cycloalkyl, phenyl, pyridinyl, piperidinyl or tetrahydropyranyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C 1-C3 alkyl group, a -NR 7R8 group or

28 EP 2 518 070 A1

a -OR8 group; wherein R7 and R8 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group;

R2 and R3 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group; 5

R4 represents a hydrogen atom, a C1-C3 haloalkyl group, or a linear or branched C1-C3 alkyl group;

R6 represents a hydrogen atom, a halogen atom, a C1-C3 haloalkyl group,a linear or branched C1-C3 alkyl group or a cyclopropyl group; 10

R5 represents a moiety of formula (II-a2), (IIb-1), (IIb-2) or (IIIa-1):

15

20

25 wherein:

$ R9, R10 and R12 independently represent a hydrogen atom or a -NR’R" group; $ R13 to R16 independently represent a hydrogen atom, a -CN group, a -C(O)-NR’R" or a -NR’R" group; $ R18 and R23 represent hydrogen or a -NR’R" group; 30 $ R’ and R" each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group; and $ Y represents -NH- or -S-; or $ Y represents a nitrogen atom and Y, R4 and the carbon atom to which both R4 and Y are bonded form a pyrrolidinyl ring.

35 [0111] In a particularly preferred embodiment, the compound of the invention is of formula (Ia)

40

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50

wherein R1, R2, R3, R4, R5, R6, Ra, Rb and n are as defined above. [0112] In an alternative particularly preferred embodiment, the compound is of formula (Ib): 55

29 EP 2 518 070 A1

5

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wherein R1, R2, R3, R4, R5, Ra, Rb and n are as defined above. [0113] Particular individual compounds of the invention include:

20 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Aminopyrimidin-4-ylamino)methyl)-5-chloro-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-5-cyclopropyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-amino-9H-purin-9-yl)methyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-aminopyrimidin-4-ylamino) methyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 4-((4-Oxo-3-o-tolyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2- 25 yl)methylamino)picolinamide; 2-((2-aminopyridin-4-ylamino)methyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((9H-purin-6-ylamino)methyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-3-cyclohexylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-amino-9H-purin-9-yl) methyl)-5-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 30 2-((9H-purin-6-ylthio)methyl)-5-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-amino-9H-purin-9-yl) methyl)-6-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((9H-purin-6-ylthio)methyl)-6-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-(1-(6-amino-9H-purin-9-yl)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(6-aminopyrimidin-4- 35 ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(2-amino-9H-purin-6-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)propylamino)pyrimidine-5-carbonitrile; (R)-2-(1-(9H-purin-6-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 40 (S)-2-(1-(2-amino-9H-purin-6-ylamino)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(6-aminopyrimidin-4-ylamino)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile; 2-(1-(6-amino-9H-purin-9-yl)ethyl)-5-methyl-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-3-o-tolyl-5-(trifluoromethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 45 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(3-methoxyphenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(2,4-difluorophenyl)pyrrolo-[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-3-benzyl-5-chloropyrrolo[1,2-f][1,2,4]-triazin-4(3H)-one; 2-((6-amino-9H-purin-9-yl)methyl)-3-phenylimidazo[1,2-f][1,2,4]triazin-4(3H)-one; 50 2-((6-amino-9H-purin-9-yl)methyl)-3-o-tolylimidazo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(pyridin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(tetrahydro-2H-pyran-4-yl)pyrrolo-[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(1-methylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(9H-Purin-6-ylamino)ethyl)-3-(3-fluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 55 (S)-4-Amino-6-(1-(3-(3-fluorophenyl)-4-oxo-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5- carbonitrile; (S)-2-(1-(9H-Purin-6-ylamino)ethyl)-3-(3,5-difluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-Amino-6-(1-(3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-

30 EP 2 518 070 A1

carbonitrile; 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-methylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-3-((1r,4r)-4-aminocyclohexyl)-5-chloropyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (R)-2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(1-phenylethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 5 (S)-2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(1-phenylethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(9H-purin-6-yl)pyrrolidin-2-yl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(pyridin-2-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(4-oxo-3-(pyridin-2-yl)-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile; 10 (S)-4-amino-6-(1-(4-oxo-3-phenyl-5-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile; (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenyl-5-(trifluoromethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(5-(difluoromethyl)-4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile; 15 (S)-2-(1-(9H-purin-6-ylamino)ethyl)-5-(difluoromethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenylimidazo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydroimidazo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile; (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-phenylimidazo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydroimidazo[1,2-f][1,2,4]triazin-2-yl)propylamino)pyrimidine-5-carboni- 20 trile; 2-(1-(9H-purin-6-ylamino)-3,3,3-trifluoropropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 4-amino-6-(3,3,3-trifluoro-1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)propylamino)pyrimidine-5- carbonitrile;

25 or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof. [0114] Examples of the preferred compounds are:

(S)-2-(1-(9H-purin-6-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(2-amino-9H-purin-6-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 30 (S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)propylamino)pyrimidine-5-carbonitrile; (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (S)-2-(1-(2-amino-9H-purin-6-ylamino)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile; (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 35 (S)-4-amino-6-(1-(3-(3-fluorophenyl)-4-oxo-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile; (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3,5-difluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5- carbonitrile; 40 (S)-2-((6-amino-9H-purin-9-yl)methyl)-5-chloro-3-(1-phenylethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(9H-purin-6-yl)pyrrolidin-2-yl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(pyridin-2-yl)pyrrolo[12-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(4-oxo-3-(pyridin-2-yl)-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile; 45 or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof. [0115] The compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be 50 used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0116] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. 55 For example, numerous protecting groups, and their introduction and removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein. [0117] The term amino-protecting group refers to a protecting group suitable for preventing undesired reactions at amino nitrogen. Representative amino- protecting groups include, but are not limited to, formyl; acyl groups, for example

31 EP 2 518 070 A1

alkanoyl groups such as acetyl; alkoxycarbonyl groups such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9- fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), and 1,1-di-(4’-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like. 5 [0118] The term hydroxy-protecting group refers to a protecting group suitable for preventing undesired reactions at a hydroxy group. Representative hydroxy-protecting groups include, but are not limited to, alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, for example alkanoyl groups, such as acetyl; arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like. 10 [0119] According to one embodiment of the present invention, compounds of general Formula (I) may be prepared by the synthetic route illustrated in Scheme 1, from compounds of Formula (Va), where the group Z 1 represents a halogen atom such as chlorine, bromine and iodine or another suitable leaving group such as methanesulfonate or trifluorometh- anesulfonate or other groups such as hydroxyl, that can be converted to suitable leaving groups by standard methods described in the literature, such as the Mitsunobu reaction and others. 15 [0120] Compounds of Formula (I) can be obtained directly from compounds of Formula (Va) by treatment of (Va) with compounds of Formula (IVa), (IVb) or (IVc) in the presence of a suitable base such as potassium carbonate, diisopropylethylamine or sodium hydride in an appropriate solvent such as tert-butanol, N,N-dimethylformamide or tetrahydrofurane at temperatures ranging from room temperature to 160 TC, with or without the use of microwaves irradiation. [0121] When Z1 is a halogen atom such as chlorine, it can be converted to another more reactive halogen atom such 20 as iodine by treating the compound with the chlorine atom with sodium iodide in acetone at a temperature from room temperature to reflux.

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[0122] Alternatively, compounds of general Formula (I) can be obtained directly from compounds of Formula (Vb), 50 where the group Y represents a -NR’- group, -O- or -S-; wherein R’ is a hydrogen atom, a hydroxy group, a C 1-C4 alkoxy group or a linear or branched C1-C4 alkyl group; as illustrated in Scheme 2. [0123] Compounds of Formula (Vb) can be treated with electrophiles of Formula (IVd) or (IVe), where the group Z1 represents a leaving group such as a halogen atom, methanesulphonate or trifluoromethanesulphonate, in the presence of a suitable base such as potassium carbonate, diisopropylethylamine or sodium hydride in an appropriate solvent such 55 as tert-butanol, N,N-dimethylformamide or tetrahydrofurane at temperatures ranging from room temperature to 220 TC, with or without the use of microwaves irradiation.

32 EP 2 518 070 A1

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[0124] Alternatively, compounds of Formula (Va) where Z1 is for instance a halogen atom can be converted to com- 20 pounds of Formula (Vb) where Y is a -NR’- group, wherein R’ is as defined above, by treating compounds (Va) with a solution of ammonia in a solvent such as methanol at a temperature between 60 to 120 TC. [0125] Compounds of general Formula (V), which comprises compounds of subformula (Va) and subformula (Vb), can be prepared directly from compounds of Formula (VII) as illustrated in Scheme 3 by treatment of compounds with Formula (VII) with the appropriate acid chlorides of Formula (VIII) in a solvent such as acetic acid at a temperature 25 ranging from room temperature to 150TC with or without the use of microwaves irradiation. [0126] In the particular case where Z2 is a chlorine atom, the compounds of Formula (V) can also be prepared by treating the compounds of Formula (VII) with 2-chloro-1,1,1-trimethoxyethane in the presence of pyridiniump -toluenesulfonate at a temperature between 50 TC and 150 TC. [0127] Alternatively, compounds of Formula (V) can be obtained in two steps from compounds of Formula (VII), 30 isolating the intermediate amides of Formula (VI). [0128] Compounds of Formula (VII) can be transformed in amides of Formula (VI) by treatment with carboxylic acids of Formula (IX) in the presence of an activating agent by methods and conditions well described in the literature, for example using EDC or HATU as an activating agent in a solvent such as tetrahydrofurane or dichloromethane or mixtures of these solvents at temperatures ranging from room temperature to 80 TC. 35 [0129] Alternatively, amides of Formula (VI) can be obtained from compounds of Formula (VII) by treatement with acid chlorides of Formula (VIII) at room temperature in a suitable solvent such as acetic acid or 1,4- dioxane or alternatively in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane. [0130] In asecond step, compounds of Formula (VI) canyield compounds of Formula (V) bytreatment with phosphorous oxychloride at temperatures ranging from room temperature to 100 TC, with or without a subsequent treatment with a 40 solution of a base such as ammonia, pirrolidine, piperidine or potassium carbonate in a solvent such as methanol, ethyl acetate or N,N-dimethylformamide at a temperature between room temperature and 100 TC. [0131] Alternatively, compounds of Formula (VI) can yield compounds of Formula (V) by treatment of compounds of Formula (VI) with the complex resulting from the treatment of triphenylphosphine with bromine in a solvent such as dichloromethane in the presence of a base such as triethylamine at a temperature from room temperature to reflux, with 45 or without a subsequent treatment with a base such as ammonia, pirrolidine, piperidine or potassium carbonate in a solvent such as methanol, ethyl acetate or N,N-dimethylformamide at a temperature between room temperature and 100 TC.

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[0132] The acid chlorides of Formula (VIII) and the carboxylic acids of Formula (IX) can be used in a protected form 30 to prevent certain functional groups from undergoing undesired reactions. In these cases, standard methods for the removal of these protecting groups can be used at the suitable step of the synthesis. Numerous protecting groups, their introduction and their removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein. [0133] Compounds of Formula (VII) can be prepared from carboxylic acids of Formula (XII) following the scheme 35 described in Scheme 4. [0134] Carboxylic acids (XII) can be activated with any activating reagent described in the literature such as thionyl chloride, oxalyl chloride, phosphorous oxychloride, 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouro- nium hexafluorophosphate(V), 3-((ethylimino)methyleneamino)-N,N-dimethylpropan-1-aminium chloride and treated with amines of Formula (XI) in the presence of a base such as diisopropylethylamine when needed in a suitable solvent 40 such as dioxane, dichloromethane, N,N-dimethylformamide or tetrahydrofurane at temperatures ranging from 0 TC to reflux to give amides of Formula (X). [0135] Subsequently, amides of Formula (X) can be aminated on the nitrogen atom in position 1 by any of the aminating reagents described in the literature, such as O-(mesitylenesulfonyl)hydroxylamine, O-(p-nitrobenzoyl)-hydroxylamine, O-(diphenylphosphinyl)-hydroxylamine, O-(2,4-dinitrophenyl)-hydroxylamine, hydroxylamine-O-sulfonic acid using a 45 suitable base such as triethylamine, potassium carbonate, sodium hydride or butyl lithium in an appropriate solvent such as N,N’-dimethylformamide, tetrahydrofurane, 1,4-dioxane at temperatures ranging from -78 to 100T C. Alternatively, the amination reaction can be carried out in a biphasic system using an aqueous solution of ammonia, sodium hydroxide, ammonium chloride and sodium hypochlorite and a suitable organic solvent such as dialkyl ethers and adding a phase transfer catalyst such as Aliquat 336® at temperatures ranging from 0 TC to room temperature. 50

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15 [0136] In another embodiment of the present invention, compounds of general Formula (I) may be prepared by the synthetic route illustrated in Scheme 5, from compounds of Formula (XV), where the group 1Z represents a halogen atom such as chlorine, bromine and iodine or another suitable leaving group such as methanesulfonate or trifluorometh- anesulfonate or other groups such as hydroxyl, that can be converted to suitable leaving groups by standard methods described in the literature, such as the Mitsunobu reaction and others. 20 [0137] Compounds of Formula (I) can be obtained from compounds of Formula (XIV) by treatment of (XIV) with the corresponding amines of Formula (XI) in the presence or not of a suitable base such as sodium hexamethyldisilazide or a Lewis acid such as trimethyl aluminium at a temperature ranging from room temperature to 150 TC in an appropriate solvent such as 1,4- dioxane, tetrahydrofurane or dichloromethane. The intermediate diamides of Formula (XIII) obtained were subsequently cyclizated to afford compounds of Formula (I) by treatment with phosphorous oxychloride at tem- 25 peratures ranging from room temperature to 100 TC, with or without a subsequent treatment with a solution of a base such as ammonia, pyrrolidine, piperidine or sodium methanethiolate in a solvent such as methanol, tetrahydrofurane or ethyl acetate at a temperature between room temperature and 100 TC. [0138] Alternatively, compounds of Formula (XIII) can yield compounds of Formula (I) by treatment of compounds of Formula (XIII) with the complex resulting from the treatment of triphenylphosphine with bromine in a solvent such as 30 dichloromethane in the presence of a base such as triethylamine at a temperature from room temperature to reflux, with or without a subsequent treatment with a base such as ammonia, pirrolidine or piperidine in a solvent such as methanol or ethyl acetate at a temperature between room temperature and 100 TC. [0139] Compounds of Formula (XIV) can be obtained directly from compounds of Formula (XV) by treatment of (XV) with compounds of Formula (IVa), (IVb) or (IVc) in the presence of a suitable base such as potassium carbonate, 35 diisopropylethylamine or sodium hydride in an appropriate solvent such astert -butanol, N,N-dimethylformamide or tetrahydrofurane at temperatures ranging from room temperature to 160T C, with or without the use of microwaves irradiation. [0140] When Z1 is a halogen atom such as chlorine, it can be converted to another more reactive halogen atom such as iodine by treating the compound with the chlorine atom with sodium iodide in acetone at a temperature from room 40 temperature to reflux.

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[0141] Compounds of general Formula (XV) can be prepared directly from compounds of Formula (XVI) as illustrated in Scheme 6 by treatment of compounds with Formula (XVI) with the appropriate acid chlorides of Formula (VIII) in a solvent such as acetic acid at a temperature ranging from room temperature to 150 TC with or without the use of micro- 30 waves irradiation. [0142] Alternatively, compounds of Formula (XV) can be obtained in two steps from compounds of Formula (XVI), isolating the intermediate amides of Formula (XVII). [0143] Compounds of Formula (XVI) can be transformed in amides of Formula (XVII) by treatment with acid chlorides of Formula (VIII) at a temperature ranging from 0TC to room temperature in a suitable solvent such as acetic acid or 35 1,4-dioxane. [0144] In a second step, compounds of Formula (XVII) can yield compounds of Formula (XV) by treatment with phosphorous oxychloride at temperatures ranging from room temperature to 100 TC in a suitable solvent such as 1,4- dioxane. Alternatively, compounds of Formula (XVII) can yield compounds of Formula (XV) by treatment of compounds of Formula (XVII) with the complex resulting from the treatment of triphenylphosphine with bromine in a solvent such as 40 dichloromethane in the presence of a base such as triethylamine at a temperature from room temperature to reflux, with or without a subsequent treatment with a base such as ammonia, pyrrolidine, piperidine or potassium carbonate in a solvent such as methanol, ethyl acetate or N,N-dimethylformamide at a temperature between room temperature and 100 TC.

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[0145] Compounds of Formula (XV) may be obtained from compounds of Formula (XII) as illustrated in Scheme 7 by 30 treatment with benzyl bromide and a suitable base such as triethylamine or caesium carbonate in an appropriate solvent such as N,N-dimethylformamide or acetonitrile at temperatures ranging from 0 to 60 TC following the protocol described elsewhere in the literature. Alternatively, compounds of Formula (XII) may be coupled with benzyl alcohol activating the carboxylic group of (XII) through the formation of the corresponding acid chloride or any other activated ester. [0146] Subsequently, esters of Formula (XIX) can be aminated on the nitrogen atom in position 1 by any of the 35 aminating reagents described in the literature, such as O-(mesitylenesulfonyl)hydroxylamine, O-(p-nitrobenzoyl)-hydroxylamine, O-(diphenylphosphinyl)-hydroxylamine, O-(2,4-dinitrophenyl)-hydroxylamine, hydroxylamine-O-sulfonic acid using a suitable base such as triethylamine, potassium carbonate, sodium hydride or butyl lithium in an appropriate solvent such as N,N’-dimethylformamide, tetrahydrofurane, 1,4-dioxane at temperatures ranging from -78 to 100T C. Alternatively, the amination reaction can be carried out in a biphasic system using an aqueous solution of ammonia, 40 sodium hydroxide, ammonium chloride and sodium hypochlorite and a suitable organic solvent such as dialkyl ethers and adding a phase transfer catalyst such as Aliquat 336® at temperatures ranging from 0 TC to room temperature. [0147] Preparation of compounds of Formula (XV) can be done by hydrogenolysis using an appropriate catalyst such as 10% palladium on charcoal in a suitable solvent such as an alkyl alcohol under a hydrogen atmosphere at pressures ranging from atmospheric pressure to 60 psi and at temperatures ranging from room temperature to 60 TC. Alternatively, 45 it is also possible to add an acid to the reaction media such as hydrochloric acid to favour the hydrogenolysis process. Also, compounds of Formula (XV) can be obtained by saponification of esters (XVIII) using an acid such as hydrochloric acid or sulphuric acid or a base such as sodium hydroxide in an appropriate solvent such as water or alkyl alcohols at temperatures ranging from room temperature to 100TC.

50

55

37 EP 2 518 070 A1

[0148] Compounds (XII) can be either commercially available compounds or can be prepared by the synthetic schemes illustrated in Schemes 8, 9 and 10. In the particular case when X represents CR 6 being R6 a C3-C7 cycloalkyl group, or a linear or branched C 1-C4 alkyl group, compounds XIIa can be prepared, as illustrated in Scheme 8, from bromopyrrol of Formula (XXIa)2 by Suzuki coupling with the corresponding alkyl or cycloalkylboronic acids in the presence of a 5 palladium catalyst such as tetrakis (triphenylphosphane) palladium(0) and appropriate base such as potassium carbonate and in a suitable solvent such as toluene at a temperature ranging from 60 TC to 150TC. Compounds of Formula (XIIa) can be obtained by simultaneous cleavage of the sulphone and ester groups of compounds of Formula (XXa) by means of a base such as lithium hydroxide in a suitable solvent or mixture of solvents such as water or tetrahydrofurane at temperatures ranging from room temperature to 220 TC, with or without the use of microwaves irradiation. Alternatively, 10 the cleavage of the sulphone and ester groups of compounds of Formula (XXa) can be done sequentially by treatment of compounds (XXa) with tetrabutylammonium fluoride in an appropriate solvent such as tetrahydrofurane at a temperature from room temperature to reflux and subsequent hydrolysis of the ester group by any of the methods well known in the literature.

15

20

25

[0149] In the particular case when X represents CR6 being R6 hydrogen or C3-C7 cycloalkyl group, or a linear or 30 branched C 1-C4 alkyl group, and R2 independently represents hydrogen or C 3-C7 cycloalkyl group, or a linear or branched C1-C4 alkyl group, compounds Xa can be prepared, as illustrated in Scheme 9, from pyrroles of Formula (XXIIIa). Pyrroles of Formula (XXIIIa) can be reacted with 2,2,2-trichloroacetyl chloride in a suitable solvent such as diethyl ether at a temperature ranging from room temperature to reflux affording ketones of Formula (XXIIa). These intermediate compounds of Formula (XXIIa) can be reacted with the corresponding amines of Formula (XI) with or without solvent in the 35 presence of a base such as triethylamine at a temperature ranging from room temperature to 150 TC to afford compounds of Formula (Xa).

40

45

50

[0150] In the particular case where X represents CR6, being R6 a trifluoromethyl group, compound of Formula (Xb) can be prepared from compound of Formula (XXIa) as illustrated in Scheme 10. The bromine atom of compound of Formula (XXIa) can be converted into a iodine atom by treatment of (XXIa) with sodium iodide in the presence of a 55 catalysts such as copper (I) iodide and a chelating amine such as trans-1,2-bis(methylamino)cyclohexane in an appropriate solvent such as 1,4- dioxane at a temperature ranging from 60 TC to reflux affording compound of Formula (XXIb). Next, treatment of compound of Formula (XXIb) with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate or any other trifluoro methylating agent using a suitable catalyst such as copper (I) iodide in the presence or not of a chelating agent such as

38 EP 2 518 070 A1

hexamethylphosphoramide and in an appropriate solvent such as N,N’-dimethylformamide afforded intermediate compound of Formula (XXb). Compounds of Formula (XXb) can be treated with amines of Formula (XI) in the presence or not of a Lewis acid such as trimethyl aluminium in an appropriate solvent such as toluene and a temperature ranging from room temperatures to 120T C yielding compounds of Formula (XXIV). Compounds of Formula (Xb) can be obtained 5 by cleavage of the sulphone group of compounds of Formula (XXIV) by means of a base such as lithium hydroxide in a suitable solvent or mixture of solvents such as water or tetrahydrofurane at temperatures ranging from room temperature to 220 TC, with or without the use of microwaves irradiation. Alternatively, the cleavage of the sulphone group of compounds of Formula (XXIV) can be done by treatment of these compounds (XXIV) with tetrabutylammonium fluoride in an appropriate solvent such as tetrahydrofurane at a temperature from room temperature to reflux. 10

15

20

25 EXAMPLES

General

[0151] The syntheses of the compounds of the invention and of the intermediates for use therein are illustrated by the 30 following Examples (1-56) (including Preparation Examples (Preparations 1-44)) are given in order to provide a person skilled in the art with a sufficiently clear and complete explanation of the present invention, but should not be considered as limiting of the essential aspects of its subject, as set out in the preceding portions of this description. [0152] Reagents, starting materials, and solvents were purchased from commercial suppliers and used as received. Concentration or evaporation refers to evaporation under vacuum using a Büchi rotatory evaporator. 35 [0153] Reaction products were purified, when necessary, by flash chromatography on silica gel (40-63 Pm) with the solvent system indicated. Purifications in reverse phase were made in a Biotage SP1® automated purification system equipped with a C18 column and using a gradient of water-acetonitrile/MeOH (1:1) (0.1 % v/v ammonium formate both phases) from 0% to 100% acetonitrile/ MeOH (1:1) in 40 column volumes. The appropriate fractions were collected and the solvents evaporated under reduced pressure and/or liofilized. 40 [0154] Preparative HPLC-MS were performed on a Waters instrument equipped with a 2767 injector/ collector, a 2525 binary gradient pump, a 2996 PDA detector, a 515 pump as a make-up pump and a ZQ4000 Mass spectrometer detector or on a Agilent 1200 Series coupled to an Agilent 6120 Mass spectrometer detector. Both systems were equipped with a Symmetry Prep C18 (19 x 300 mm, 7 Pm) column or a XBridge Prep C18 (19 x 100 mm, 5 Pm) column. The mobile phase was formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid 45 (0.5 mL), ammonia (0.125 mL) and water (1000 mL) (A), the specific gradients used are specified in each particular case. The flow rate was 20 mL/min. [0155] Purity and MS identification was performed in a Waters 2795 system coupled to a 2996 Diode array detector and to a Waters ZQmass spectrometerdetector or in a Waters Acquity UPLCsystem coupled to a SQD massspectrometer detector. The injection volume was 5 microliter on the HPLC and 0.5 microliter on the UPLC. Chromatograms were 50 processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative elec- trospray ionization. The mobile phase was formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid (0.5 mL), ammonia (0.125 mL) and water (1000 mL) (A) and a gradient between 0 to 95% of B was used. Columns: HPLC: Waters Symmetry (2.1x50mm, 3.5 Km); UPLC: ACQUITY UPLC BEH C- 18 (2.1x50mm, 1.7 Km) 55 [0156] 1H Nuclear Magnetic Resonance Spectra were recorded on a Varian Gemini-2000 spectrometer operating at a frequency of 300 MHz for the 1H spectra or in a Varian Mercury plus operating at a frequency of 400 MHz for the 1H spectra. Samples were dissolved in the specified deuterated solvent. Tetramethylsilane was used as reference.

39 EP 2 518 070 A1

Abbreviations:

[0157]

5 DMF Dimethylformamide

DMSO Dimethylsulfoxide

CDCl3 Deuterated chloroform 10 NMR Nuclear magnetic resonance

sSinglet

15 d Doublet

dd Doublet doublet

td Triple doublet 20 br Broad

q Quarted

25 t Triplet

m Multiplet

LRMS Low resolution mass spectrometry 30 hhour

min minutes

35 DMF N,N-dimethylformamide

DCM dichloromethane, methylene chloride

AcOEt ethyl acetate 40 DMSO dimethylsufoxide

EDC·HCl 3-((ethylimino)methyleneamino)-N,N-dimethylpropan-1-aminium chloride

45 THF tetrahydrofurane

DIEA diisopropylethyamine

HOBt 1-Hydroxybenzotriazole hydrate 50 MeOH methanol

DPPONH2 P,P-diphenylphosphinic amide

55 PPTS pyridinium p-toluenesulphonate

Pd(PPh3)4 Tetrakis(triphenylphosphane) palladium(0)

40 EP 2 518 070 A1

HMPA hexamethylphosphoramide

Celite® diatomaceous earth

5 PREPARATION 1

1-Amino-3-chloro-N-phenyl-1H-pyrrole-2-carboxamide

a) 3-Chloro-N-o-tolyl-1H-pyrrole-2-carboxamide 10 [0158] A suspension of the 3-chloro-1H-pyrrole-2-carboxylic acid1 (1,2 g, 8,3 mmol) in thionyl chloride (6 mL) was heated to reflux during 30 minutes. At the end of this period, volatiles were removed by distillation under reduced pressure coevaporating with tetrahydrofurane a couple of times. The residue obtained after evaporation was dissolved in a small amount of dry dioxane and was added to a solution of o-toluidine (1,33 g, 12,4 mmol) and DIEA (4,32 mL, 25 mmol) in 15 70 mL of dry 1,4- dioxane at 0TC. Once the addition was finished, the reaction crude was heated to 60 TC during 2 hours. Afterwards, this crude was evaporated under vacuum and the residue was taken up with ethyl acetate and washed successively with water, saturated solution of sodium carbonate, water, hydrochloric acid 2N, water and brine. The organic phase was separated, dried (sodium sulphate, Na 2SO4) and concentrated under vacuum to give a residue that was triturated with hexane affording 950mg (88% yield) of a solid after filtration. 20 LRMS (m/z): 235 (M+1)+.

b) 1-Amino-3-chloro-N-phenyl-1H-pyrrole-2-carboxamide

[0159] In a 100 mL three-necked flask it was placed 11 mL of a 28% aqueous solution of sodium hydroxyde, 4,1 mL 25 of a 28% ammonium hydroxide solution, 1,23 g of ammonium chloride and 0,12 mL of Aliquat 336. Afterwards, a solution of 3-chloro-N-o-tolyl-1H-pyrrole-2-carboxamide (0,9 g, 3,84 mmol) in 30 mL of diethyl ether and 30 mL of methyl tert-butyl ether was added and placed at 0TC affording a suspension. Over this suspension, a 10% aqueous solution of sodium hypochlorite (26 mL) was added drop wise with vigorous stirring mateining the temperature during 20 min. more. Sub- sequently, the reation mixture was stirred atroom temperatureduring a further 1,5 h producing the consumption of the 30 starting material. Next, the reaction crude was diluted with ethyl acetate until no suspended material was observed. The layers were separated and the organic phase was washed with a 25% aqueous solution of sodium thiosulphate, water and brine, dried (Na2SO4) and concentrated under vacuum to give a residue that was triturated with hexane to produce a solid (870 mg, 86 yield) after filtration. LRMS (m/z): 250 (M+1)+. 35 1H NMR (400 MHz, dmso) δ 11.05 (s, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.28 - 7.13 (m, 2H), 7.07 - 6.96 (m, 2H), 6.82 (s, 2H), 6.16 (d, J = 3.0 Hz, 1H), 2.29 (s, 3H).

PREPARATION 2

40 5-Chloro-2-(chloromethyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0160] To a suspension of 1-amino- 3-chloro-N-phenyl-1H-pyrrole-2-carboxamide (0,56 g, 2,24 mmol) in glacial acetic acid (19 mL) was added 0,93 mL (11,7 mmol) of chloroacetyl chloride getting a solution. The reation mixture was stirred during 2 hours to produce the desired compound. Then, the reaction mixture was poured into ice-water precipitating a 45 solid that was filtered and washed with more water. This solid was taken up with ethyl acetate and the organic phase was washed with 4% aqueous solution of sodium bicarbonate and water, dried and evaporated under vacuum to yield 650 mg (89% yield) of 3-chloro-1-(2-chloroacetamido)-N-o-tolyl-1H-pyrrole-2-carboxamide as a solid. [0161] This intermediate compound was dissolved in toluene (40 mL) and 50 mg of pyridinium p-toluenesulphonate (PPTS) were added heating the reaction to reflux with a Dean- Stark to remove the water from the reaction media. After 50 40 hours, the starting material has disappeared and then, the reaction was elaborated by cooling down toroom temper- atureand adding ethyl acetate. This organic phase was washed with water, 4% aqueous solution of sodium bicarbonate and brine and dried (Na2SO4). Removal of the volatiles under vacuum produced a residue of 580 mg of the desired product (85% yield). LRMS (m/z): 308 (M+1)+. 55 1 H NMR (400 MHz, CDCl3) δ 7.48 - 7.32 (m, 4H), 7.23 (d, J = 7.8 Hz, 1H), 6.56 (d, J = 3.0 Hz, 1H), 4.21 (d, J = 12.1 Hz, 1H), 4.04 (d, J = 12.1 Hz, 1H), 2.22 (s, 3H).

41 EP 2 518 070 A1

PREPARATION 3

2-(Aminomethyl)-5-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

5 [0162] A solution of the starting 5- chloro-2-(chloromethyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (200 mg, 0,65 mmol) in a 7M ammonia solution in methanol was heated at 85TC with stirring in a sealed tub during 4 h. At the end of this period, the volatiles were removed under vacumm and the residue was taken-up with ethyl acetate and washed with a 4% aqueous solution of sodium bicarbonate, water and brine. The organic layer was dried (Na2SO4) and concentrated to dryness giving 140 mg of a residue corresponding to the title compound of the preparation (76% yield). 10 LRMS (m/z): 289 (M+1)+.

PREPARATION 4

3-Cyclopropyl-1H-pyrrole-2-carboxylic acid 15 a) Methyl 3-cyclopropyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate

[0163] In a schlenk flask, a mixture of methyl 3- bromo-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate2 (1,45 g, 4,2 mmol), cyclopropylboronic acid (1,09 g, 12,6 mmol) and potasium carbonate (1,75 g, 12,7 mmol) was suspended in toluene 20 and the system was desgassed doing 3 cycles of vacuum-Ar. Next, tetrakis(triphenylphosphane) palladium(0) (Pd (PPh3)4) was added as a solid and 3 new cycles of vacuum-Ar were done stirring the reaction at 100TC overnight. At the end of this period, the starting material was conpsumed and the reaction was worked-up pouring the crude over water and extracting the resulting mixture with ethyl acetate (3x50 mL). The organic solution was washed with water and brine, dried over Na 2SO4 and concentrated under vacuum to give a residue that was purified by flash chromatography 25 silica (hexane/ethyl acetate). After the purification were obtained 976 mg of the title compound (76% yield). LRMS (m/z): 306 (M+1)+.

b) 3-Cyclopropyl-1H-pyrrole-2-carboxylic acid

30 [0164] To a suspension of the starting methyl 3-cyclopropyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (0,9 g, 3 mmol) in tetrahydrofurane (4,6 mL) and water (2,3 mL) was added lithium hydroxide (0,29 g, 12 mmol) and this mixture was heated to 100TC in a microwave vial during 4 hours. Next, the reaction mixture was poured into water (50 mL) and this aqueous phase was washed with diethyl ether (2x). Afterwards, the aqueous layer was acidified until pH=3 by adding solid phosphoric acid and extracted with ethyl acetate (3x). The organic solution was washed with water and brine, dried 35 (Na2SO4) and concentrated in vacuo to give 370 mg of the title compound. LRMS (m/z): 150 (M-1)-.

PREPARATION 5

40 1-Amino-3-cyclopropyl-N-o-tolyl-1H-pyrrole-2-carboxamide

a) 3-Cyclopropyl-N-o-tolyl-1H-pyrrole-2-carboxamide

[0165] To a suspension of the 3- cyclopropyl-1H-pyrrole-2-carboxylic acid (50 mg, 0,33 mmol) in dry dichloromethane 45 (0,4 mL) was added a solution of oxalyl chloride (0,04 mL, 0,37 mmol) in 0,3 mL of dichloromethane atroom temperature and 3 drops of N,N-dimethylformamide. After 1,5 h at this temperature, the mixture was concentrated under vacuum and the residue was redissolved in dichloromethane (1 mL). To this solution was added a solution oof-toluidine in dichloromethane (0,2 mL) and the mixture was stirred at room temperature overnight. The reaction was worked-up diluting with dichloromethane and washing with sodium bicarbonate (2x) and brine. The organic phase was dried and 50 concentrated to give 74 mg of the title compound (88% yield). LRMS (m/z): 241 (M+1)+.

b) 1-Amino-3-cyclopropyl-N-o-tolyl-1H-pyrrole-2-carboxamide.

55 [0166] This compound was prepared starting from 3-cyclopropyl-N-o-tolyl-1H-pyrrole-2-carboxamide (106 mg, 0,44 mmol) and following the experimental procedure described in Preparation 1b to afford 113 mg (93% yield) of the title compound. LRMS (m/z): 256 (M+1)+.

42 EP 2 518 070 A1

PREPARATION 6

2-(Chloromethyl)-5-cyclopropyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

5 [0167] This compound was prepared starting from 1-amino-3-cyclopropyl-N-o-tolyl-1H-pyrrole-2-carboxamide (130 mg, 0,4 mmol) and following the experimental procedure described in Preparation 1c to afford 107 mg (73% yield) of the title compound. LRMS (m/z): 314 (M+1)+.

10 PREPARATION 7

1-amino-N-o-tolyl-1H-pyrrole-2-carboxamide

a) N-o-tolyl-1H-pyrrole-2-carboxamide 15 [0168] 15.0 g (135 mmol) of 1 H-pyrrol 2-carboxylic acid (purchased from Aldrich ®, cat. no. P7,360-9) were suspended in a mixture of DMF (1.2 mL) and dichloromethane (150 mL). To this solution, 18 mL (207 mmol) of oxalyl chloride in dichloromethane (105 mL) were added dropwise over 30 minutes. The reaction was stirred two hours and then concentrated under reduced pressure to dryness. 20 [0169] The residual black oil was redissolved in dichloromethane (150 mL) and a solution of 15.9 g (148 mmol) of o- toluidine in dichloromethane (16 mL) was added dropwise. The reaction was stirred overnight then the solution was washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was concentrated in vacuo. The product was purified by flash chromatography (30% AcOEt in hexane) to give 15.45 g (100% yield) of the title compound. LRMS (m/z): 201 (M+1)+. 25 b) 1-amino-N-o-tolyl-1H-pyrrole-2-carboxamide

[0170] Prepared from 14.25 g (71.2 mmol) of N-o-tolyl-1H-pyrrole-2-carboxamide following the experimental procedure described in preparation 1 b. The crude product was suspended in diisopropyl ether and sonicated and the solid was 30 filtered and washed with diethylether to give 10.04 g (66% yield) of the title compound. LRMS (m/z): 216 (M+1)+. 1H NMR (400 MHz, DMSO) δ 11.15 (s, 1 H), 8.06 (d, J = 7.7 Hz, 1H), 7.26 - 7.15 (m, 2H), 7.02 (t, J = 6.8 Hz, 1H), 6.96 (t, J = 2.3 Hz, 1H), 6.79 - 6.72 (m, 3H), 6.05 (dd, J = 4.2, 2.7 Hz, 1H), 2.29 (s, 3H).

35 PREPARATION 8

2-(chloromethyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0171] 9.5 mL (119 mmol) of 2-chloroacetyl chloride were added to a suspension of 5.14 g (23.9 mmol) of 1-amino- 40 N-o-tolyl-1H-pyrrole-2-carboxamide in 188 mL of glacial acetic acid, and the mixture was stirred at 120 TC for 3.5 hours. Then, the reaction mixture was cooled down to room temperature and it was concentrated in vacuo. The residue obtained was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, water and brine. It was dried over magnesium sulphate, filtered and concentrated in vacuo. 4.99 g (65% yield) of the title compound were obtained. 45 LRMS (m/z): 274 (M+1)+. 1H NMR (400 MHz, DMSO) δ 7.66-7.83 (m, 1H), 7.29 - 7.60 (m, 4H), 7.05 (d, J = 4.30 Hz, 1H), 6.59 - 6.78 (m, 1H), 4.31 (dd, J = 10.55 Hz, 2H), 2.10 (s, 3H).

PREPARATION 9 50 2-(aminomethyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0172] A solution of 450 mg (1.64 mmol) of 2-(chloromethyl)- 3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one in 20 mL of a 7M solution of ammonia in methanol was heated at 85 TC in a sealed tube overnight, then cooled to room temperature 55 and concentrated in vacuo to afford the title 491 mg (100% yield) of the title compound. LRMS (m/z): 255 (M+1)+. 1H NMR (400 MHz, DMSO) δ 7.65 - 7.75 (m, 1 H), 7.32 - 7.52 (m, 4 H), 7.03 (d, J = 3.91 Hz, 1 H), 6.42 - 6.97 (m, 3 H), 2.09 (s, 3 H).

43 EP 2 518 070 A1

PREPARATION 10

1-Amino-N-cyclohexyl-1H-pyrrole-2-carboxamide

5 a) N-Cyclohexyl-1H-pyrrole-2-carboxamide

[0173] The mixture of methyl 1H-pyrrole-2-carboxylate (2,5 g, 20 mmol) and cyclohexylamine (13,8 mL, 120 mmol) was heated at 160TC in a sealed tub overnight with stirring. Next day, volatiles were removed under reduced pressure and the residue was taken-up with ethyl acetate and washed water, acidic water (pH=1) and brine. The organic layer 10 was dried (Na2SO4) and concentrated in vacuo to give 1,88 g of a residue that was purified by flash chromatography silica (hexane/ethyl acetate) to obtain 0,88 g of the title compound (23% yield). LRMS (m/z): 193 (M+1)+.

b) 1-Amino-N-cyclohexyl-1H-pyrrole-2-carboxamide 15 [0174] This compound was prepared starting from benzyl N-cyclohexyl-1H-pyrrole-2-carboxamide (880 mg, 4,6 mmol) and following the experimental procedure described in Preparation 1 b to afford 700 mg (74% yield) of the title compound that was used in the next step without any further purification. LRMS (m/z): 208 (M+1)+. 20 1H NMR (400 MHz, dmso) δ 8.53 (d, J = 7.8 Hz, 1H), 6.84 - 6.77 (m, 1H), 6.61 (dd, J = 4.2, 2.0 Hz, 1H), 6.55 (s, 2H), 5.91 (dd, J = 4.2, 2.6 Hz, 1H), 3.80 - 3.64 (m, 1H), 1.87 - 1.48 (m, 5H), 1.39 - 1.20 (m, 5H).

PREPARATION 11

25 N-cyclohexyl-1H-pyrrole-2-carboxamide

[0175] To a solution of 1-amino- N-cyclohexyl-1H-pyrrole-2-carboxamide (160 mg, 0,77 mmol) in 1,4- dioxane (10 mL) was added 77 PL (0,97 mmol) of chloroacetyl chloride and the reation mixture was stirred at 100 TC during 1 h. Afterwards, the mixture was concentrated to dryness and the residue was dissolved in phosphorous oxychloride (3 mL) and heated 30 to 50TC with stirring overnight. Next day, the cooled reaction mixture was poured slowly into an aqueous solution of potassium carbonate. The resulting mixture was extracted with ethyl acetate and the organic layer was washed with water (2x), dried (Na 2SO4) and concentrated to afford 120 mg of a residue that was used in the next step without further purification. LRMS (m/z): 266 (M+1)+. 35 PREPARATION 12

3-methyl-1H-pyrrole-2-carboxylic acid

40 [0176] 2.0 g (14.37 mmol) of methyl 3-methyl-1H-pyrrole-2-carboxylate (purchased from Otava Chemicals®, cat. no. 1056278) were dissolved in 50 mL of methanol and 21.5 mL of a 2N aqueous solution of sodium hydroxide were added. The mixture was stirred at room temperature overnight and then at 60 TC for 20 hours. Then the methanol was evaporated in vacuo and the remaining aqueous solution was neutralized with 21.5 mL of a 2N solution of hydrochloric acid. The product was extracted with a 95:5 mixture of chloroform/methanol and the organic phase was washed with brine, dried 45 over magnesium sulphate, filtered and evaporated under vacuum. 1.38 g (77% yield) of the title compound were obtained as a brown solid. LRMS (m/z): 126 (M+1)+. 1H NMR (400 MHz, DMSO) δ 12.06 (s, 1H), 11.30 (s, 1H), 6.84 - 6.75 (m, 1H), 6.02-5.93 (m, 1H), 2.24 (s, 3H).

50 PREPARATION 13

1-amino-3-methyl-N-o-tolyl-1H-pyrrole-2-carboxamide

a) 3-methyl-N-o-tolyl-1H-pyrrole-2-carboxamide 55 [0177] 2.0 g (15.98 mmol) of 3- methyl-1H-pyrrole-2-carboxylic acid were dissolved in 50 mL of dichloromethane. 5.60 mL (63.9 mmol) of oxalyl chloride were added, followed by 5 drops of DMF. The reaction mixture was stirred at room temperature for 2 hours and then the solvents were evaporated. The black oil residue was dissolved in 50 mL of

44 EP 2 518 070 A1

dichloromethane and 6.85g (63.9 mmol)of o-toluidinewere added dropwise. The reaction was stirred at room temperature for 1 hour and then the solvent was evaporated. The crude product was purified by flash chromatography (dichloromethane to dichloromethane/methanol 95:5) and then triturated in diisopropylether to give 2.97 g (87% yield) of the title compound as a brown solid. 5 LRMS (m/z): 215 (M+1)+.

b) 1-amino-3-methyl-N-o-tolyl-1H-pyrrole-2-carboxamide

[0178] 3-methyl-N-o-tolyl-1H-pyrrole-2-carboxamide (1.5 g, 7.00 mmol) was dissolved in 60 mL of DMF. 294 mg (7.35 10 mmol) of sodium hydride (60 wt% dispersion in mineral oil) were added and the reaction mixture was stirred at room temperature for 1 hour. Then O-(mesitylsulfonyl)hydroxylamine (1.658 g, 7.70 mmol) were added and the reaction mixture was stirred for 30 minutes. The solvent was evaporated to dryness and the crude product was purified by flash chromatography (0 to 50% heptane/AcOEt) to give 1.17 g (73% yield) of the title compound as a yellow solid. LRMS (m/z): 230 (M+1)+. 15 PREPARATION 14

2-(chloromethyl)-5-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H-one

20 [0179] 140 mg (0.61 mmol) of 1- amino-3-methyl-N-o-tolyl-1H-pyrrole-2-carboxamide were dissolved in 3 mL of acetic acid. Chloroacetyl chloride (0.245 mL, 3.05 mmol) was added under vigorous stirring and the reaction mixture was then heated at 120 TC for 30 minutes. Then the mixture was allowed to cool to room temperature, poured into a mixture of water/ice and extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulphate, filtered and evaporated to dryness. The crude product was purified 25 by flash chromatography (0 to 40% heptane/ethyl acetate) to give 125 mg (71% yield) of the title compound as a white solid. LRMS (m/z): 288 (M+1)+.

PREPARATION 15

30 2,2,2-Trichloro-1-(4-methy)-1H-pyrrol-2-yl)ethanone

[0180] To a solution of 2,2,2-trichloroacetyl chloride (5,05 mL, 45,3 mmol) in dry diethyl ether (12 mL) was slowly added a solution of 3-methyl-1H-pyrrole (3,15 g, 39.37 mmol) in 30 mL of dry diethyl ether during 1 h 15 min. Once the addition was finished, the reaction mixture was stirred at 45 TC during 1 hour 30 minutes more. Next, more diethyl ether 35 was added and the organic phase was washed with an aqueous solution of potassium carbonate to neutralize de media, water and brine. The organic phase was dried (Na 2SO4) and concentrated to dryness to give a residue that was purified by flash chromatography silica (hexane/dichloromethane) to afford 4,7 g of the title compound (55% yield). LRMS (m/z): 224 (M-1)-.

40 PREPARATION 16

1-Amino-4-methyl-N-o-tolyl-1H-pyrrole-2-carboxamide

a) 4-Methyl-N-o-tolyl-1H-pyrrole-2-carboxamide 45 [0181] A solution of 2,2,2- trichloro-1-(4-methyl-1H-pyrrol-2-yl)ethanone (2 g, 8,8 mmol) in a mixture of o- toluidine (1,76 mL, 16,5 mmol) and triethylamine (2,1 mL, 15,07 mmol) under argon was heated to T80C with stirring during 75 h. Afterwards, the reaction mixture was concentrated to dryness giving a residue that ws treated with hexane and the resulting soid filtered to afford 848 mg of the title compound (45% yield). 50 LRMS (m/z): 215 (M+1)+.

b) 1-Amino-4-methyl-N-o-tolyl-1H-pyrrole-2-carboxamide

[0182] This compound was prepared starting from 4-methyl-N-o-tolyl-1H-pyrrole-2-carboxamide (845 mg, 3,9 mmol) 55 and following the experimental procedure described in Preparation 1 b to afford 516 mg (54% yield) of the title compound that was used in the next step without any further purification. LRMS (m/z): 230 (M+1)+.

45 EP 2 518 070 A1

PREPARATION 17

2-(chloromethyl)-6-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

5 [0183] 465 mg (2.03 mmol) of 1- amino-4-methyl-N-o-tolyl-1H-pyrrole-2-carboxamide were dissolved in 10 mL of acetic acid and 759 PL (9.53 mmol) of chloroacetyl chloride were added. The mixture was stirred at 120T C for 4 hours and the solvent was removed under vacuo. The residue was dissolved in AcOEt and washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and evaporated under vacuum. 660 mg (69% yield) of the title compound were obtained as a beige solid. 10 + LRMS (m/z): 288 (M+1) .

PREPARATION 18

1-amino-N-phenyl)-1H-pyrrole-2-carboxamide 15 a) Nphenyl-1H-pyrrole-2-carboxamide

Prepared following the experimental method described in preparation 1 a starting from

20 [0184] 10.0 g (90.0 mmol) of 1 H-pyrrole-2-carboxylic acid (purchased from Aldrich®, cat. no. P7,360-9) and 9.22 g (99.0 mmol) of aniline. 13.0 g (78% yield) of the title compound were obtained as a brownish solid. LRMS (m/z): 187 (M+1)+.

b) 1-amino-N-phenyl)-1H-pyrrole-2-carboxamide 25 [0185] The title compound was prepared from 12.9 g (69.8 mmol) ofN -phenyl-1H-pyrrole-2-carboxamide following the experimental procedure described in preparation 1 b. 10.3 g (73% yield) of the title compound were obtained as a solid. LRMS (m/z): 202 (M+1)+. 1H NMR (400 MHz, DMSO) δ 10.74 (s, 1 H), 7.67 (d, J = 7.7 Hz, 2H), 7.33 (t, J = 7.9 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1 H), 30 6.95 (t, J = 2.2 Hz, 1 H), 6.83 (dd, J = 4.2, 1.9 Hz, 1 H), 6.64 (s, 2H), 6.02 (dd, J = 4.2, 2.7 Hz, 1 H).

PREPARATION 19

2-(1-chloroethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one 35 [0186] 2.50 mL (25.75 mmol) of 2- chloropropanoyl chloride was added to a solution of 1-amino- N-phenyl-1H-pyrrole- 2-carboxamide in glacial acetic acid and it was stirred at room temperature for 1 hour. Then it was concentrated in vacuo and the remaining acetic acid was co- evaporated with cyclohexane. 20 mL (218 mmol) of phosphorous oxychloride were added to the residue obtained and the resulting solution was heated at 125T C. After 10 hours it was allowed to cool 40 down to room temperature and the reaction mixture was carefully poured into a cold over-saturated aqueous solution of sodium bicarbonate. The aqueous solution was extracted with ethyl acetate, and the organic phases were collected together and washed with brine and then concentrated in vacuo. The residue obtained was dissolved in a mixture of hexane and ethyl acetate (10:1), filtered through silica and concentrated in vacuo. This residue was dissolved in 4 mL of a 7M solution of ammonia in methanol and then was heated to 60 TC overnight. The reaction mixture was concentrated 45 in vacuo to obtain 75 mg (6% yield) of the title compound. LRMS (m/z): 274 (M+1)+.

PREPARATION 20

50 (S)-2-(1-aminopropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

a) (S)-tert-butyl 1-oxo-1-(2-(phenylcarbamoyl)-1H-pyrrol-1-ylamino)butan-2-ylcarbamate

[0187] 2.0 g (9.94 mmol) of 1-amino-N-phenyl-1H-pyrrole-2-carboxamide, 2.45 g (12.05 mmol) of (S)-2-(tert-butoxy- 55 carbonylamino) butanoic acid (purchased from Aldrich®, cat. no. 15533) and 1.90 g (12.24 mmol) of EDC·HCl were dissolved in a mixture of 90 mL of THF and 30 mL of dichloromethane. The resulting solution was heated at T55C overnight. Then the solvents were evaporated and the crude residue was taken up in dichloromethane and washed with an aqueous solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulphate, filtered

46 EP 2 518 070 A1

and the solvent was evaporated. The solid obtained was triturated in diethyl ether to furnish 2.47 g (64% yield) of the title compound. LRMS (m/z): 387 (M+1)+.

5 b) (S)-2-(1-aminopropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0188] 1.0 g (2.59 mmol) of S ()-tert-butyl 1-oxo-1-(2-(phenylcarbamoyl)-1H-pyrrol-1-ylamino)butan-2-ylcarbamate were suspended in 13 mL of phosphorous oxychloride and heated to 80 TC for 6 hours. Then the excess reagent was removed under vacuum and the residue was taken up in AcOEt and treated with an aqueous solution of sodium bicar- 10 bonate. The two layers were separated and the aqueous phase was extracted with more AcOEt. The combined organic extracts were washed with brine, dried and the solvent was evaporated to give 1.2 g of a black oil. This intermediate was purified by flash chromatography (0-100% AcOEt in hexane) to give 421 mg of a yellow syrup that was treated with 50 mL of a 7M methanolic solution of ammonia at 80 TC in a sealed vessel. The solvent was then evaporated and the final product was purified by flash chromatography (0-100% AcOEt in hexane) to give 125 mg (11% yield) of the title 15 compound. LRMS (m/z): 269 (M+1)+. 1H NMR (400 MHz, DMSO) δ 8.23 (s, 1 H), 7.71 - 7.37 (m, 5H), 6.94 (dd, J = 4.3, 1.7 Hz, 1 H), 6.60 (dd, J = 4.3, 2.7 Hz, 1 H), 3.14 (dd, J = 7.5, 5.6 Hz, 1 H), 1.81 - 1.64 (m, 1 H), 1.48 - 1.32 (m, 1 H), 0.72 (t, J = 7.4 Hz, 3H).

20 PREPARATION 21

2-(1-aminoethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

a) tert-butyl 1-oxo-1-(2-(phenylcarbamoyl)-1H-pyrrol-1-ylamino)propan-2-ylcarbamate 25 [0189] The title compound was prepared following the experimental procedure described in preparation 20a from 1.50 g (7.45 mmol) of 1-amino-N-phenyl-1H-pyrrole-2-carboxamide and 1.82 g (8.95 mmol) of racemic 2-(tert-butoxycarbonylamino)butanoic acid (purchased from ABCR, cat. no. AB154485). After recristallysation of the crude product in diethylether, 2.43 g (84% yield) of the title compound were obtained. 30 LRMS (m/z): 387 (M+1)+.

b) 2-(1-aminopropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0190] 1.0 g (2.59 mmol) of tert-butyl 1-oxo-1-(2-(phenylcarbamoyl)-1H-pyrrol-1-ylamino)butan-2-ylcarbamate were 35 suspended in 16 mL of phosphorous oxychloride and heated to 80 TC for 6 hours. Then the mixture was evaporated to dryness under vacuum the residue was taken up in chloroform and treated with an aqueous solution of sodium bicarbonate. The two layers were separated and the aqueous phase was extracted with more chloroform. The combined organic extracts were washed with brine, dried and the solvent was evaporated. This intermediate was treated with a solution of 0.72 g (5.18 mmol) of potassium carbonate in DMF at 60 TC for 2.5 hours. Then the mixture was evaporated 40 to dryness and the crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain the title compound (70 mg, 10% yield) as a solid. LRMS (m/z): 269 (M+1)+.

45 PREPARATION 22

(S)-2-(1-aminoethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H-one

a) (S)-tert-butyl 1-oxo-1-(2-(phenylcarbamoyl)-1H-pyrrol-1-ylamino)propan-2- ylcarbamate 50 [0191] 2.00 g (9.94 mmol) of 1-amino-N-phenyl-1H-pyrrole-2-carboxamide were dissolved in 50 mL of DMF. To this solution, 2.07 g (10.94 mmol) of S()-2-(tert-butoxycarbonylamino)propanoic acid (purchased from Aldrich®, cat. no. 13,451-1) and 2.10 g (10.95 mmol) of EDC·HCl were added and the resulting reaction mixture was stirred at room temperature overnight. The solvent was then evaporated under vacuum, the residue was taken up in ethyl acetate and 55 the organic solution was washed with an aqueous solution of sodium bicarbonate and brine, it was dried over magnesium sulphate, filtered and the solvent was evaporated. The product was purified by flash chromatography (0-5% methanol in dichloromethane). 2.21 g (60% yield) of the final product were obtained as a white solid. LRMS (m/z): 373 (M+1)+.

47 EP 2 518 070 A1

1 H NMR (400 MHz, CDCl3) δ 10.11 (s, 1 H), 7.74 (s, 1 H), 7.55 - 7.48 (m, 2H), 7.36 - 7.28 (m, 2H), 7.15 - 7.07 (m, 1 H), 7.03 (dd, J = 2.9, 1.7 Hz, 1H), 6.67 (dd, J = 4.3, 1.7 Hz, 1 H), 6.15 (dd, J = 4.2, 2.9 Hz, 1 H), 5.08 (d, J = 7.5 Hz, 1 H), 4.40 (s, 1 H), 1.46 (s, 9H), 1.44 (d, J = 7.1 Hz, 3H).

5 b) (S)-2-(1-aminoethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0192] 2.21 g (5.93 mmol) of ( S)-tert-butyl 1-oxo-1-(2-(phenylcarbamoyl)-1H-pyrrol-1-ylamino)propan-2-ylcarbamate were treated with 27 mL of phosphorous oxychloride at 80T C for 6 hours and then it was evaporated under vacuum until a dark solid formed. This residue was dissolved with chloroform and then treated with an aqueous solution of sodium 10 bicarbonate. After stirring the mixture for 1 hour, the two layers were separated and the organic phase was washed with water and brine, dried over magnesium sulphate and the solvent was evaporated under vacuum. The residue was then treated in a sealed vessel with 30 mL of a 7M methanolic solution of ammonia at 80 TC overnight. The solvent was then evaporated and the product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain the title compound (350 mg, 23%) 15 as a white solid. LRMS (m/z): 255 (M+1)+. 1 H NMR (400 MHz, CDCl3) δ 7.58 - 7.49 (m, 3H), 7.41 (dd, J = 2.6, 1.7 Hz, 1 H), 7.32 - 7.26 (m, 2H), 7.07 (dd, J = 4.3, 1.7 Hz, 1 H), 6.56 (dd, J = 4.3, 2.7 Hz, 1 H), 3.67 (q, J = 6.6 Hz, 1 H), 1.30 (d, J = 6.6 Hz, 3H).

20 PREPARATION 23

1-amino-3-methyl-N-phenyl-1H-pyrrole-2-carboxamide

a) 3-methyl)-N-phenyl-1H-pyrrole-2-carboxamide 25 Prepared following the experimental method described in preparation 1 a starting from

[0193] 1.38 g (11.3 mmol) of 3- methyl-1H-pyrrole-2-carboxylic acid and 1.13 g (12.13 mmol) of aniline. After purification by flash chromatography (0-40% AcOEt in hexane), 1.08 g(49% yield) of the title compound wereobtained as a white solid. 30 LRMS (m/z): 202 (M+1)+.

b) 1-amino-3-methyl-N-phenyl-1H-pyrrole-2-carboxamide

[0194] The title compound was prepared from 1.08 g (5.39 mmol) of 3-methyl-N-phenyl-1H-pyrrole-2-carboxamide 35 following the experimental procedure described in preparation 1 b. 1.16 g (47% yield) of the title compound were obtained as a solid. LRMS (m/z): 216 (M+1)+. 1 H NMR (400 MHz, cdcl3) δ 9.24 (s, 1 H), 7.63 - 7.56 (m, 2H), 7.37 - 7.30 (m, 2H), 7.14 - 7.06 (m, 1 H), 6.79 (d, J = 2.7 Hz, 1 H), 5.94 (d, J = 2.3 Hz, 1 H), 5.49 (s, 2H), 2.44 (s, 3H). 40 PREPARATION 24

2-(1-chloroethyl)-5-methyl-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

45 [0195] To a solution of 1.13 g (5.25 mmol) of 1- amino-3-methyl-N-phenyl-1H-pyrrole-2-carboxamide in 45 mL of acetic acid were added 2.54 mL (26.21 mmol) of 2-chloropropanoyl chloride. The reaction was stirred at room temperature for 1 hour and then the solvent was removed in vacuo. The dark oil residue was treated with 20 mL of phosphorous oxychloride, and the mixture was heated to reflux for 16 hours and then it was evaporated under vacuum to dryness. The resulting residue was redissolved in dichloromethane and the organic solution was treated with a saturated aqueous 50 solution of sodium bicarbonate. This mixture was vigorously stirred until the gas release stopped and the two layers were separated. The organic layer was washed with water and brine, dried over magnesium sulphate and the solvent was evaporated. The dark oil that resulted was treated with 40 mL of a 7M ammonia solution in methanol in a sealed vessel at 60 TC overnight. The solution was then evaporated to dryness and the product was purified by flash chromatography (0-5% methanol in dichloromethane) to furnish 0.28 g (18% yield) of the title compound as a white solid. 55 LRMS (m/z): 288 (M+1)+.

48 EP 2 518 070 A1

PREPARATION 25

2-(1-iodoethyl)-5-methyl-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

5 [0196] 276 mg (0.96 mmol) of 2-(1- chloroethyl)-5-methyl-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one were dissolved in 10 mL of acetone and 287 mg (1.91 mmol) of sodium iodide were added. The reaction was stirred at 65 TC for 8 hours and at room temperature overnight. The solvent was evaporated to dryness under vacuum and the residue was dissolved in ethyl acetate. This solution was washed twice with water and brine, dried over magnesium sulphate and the solvent was evaporated. 340 mg (94% yield) of the title product were obtained as a brownish solid. 10 LRMS (m/z): 380 (M+1)+. 1H NMR (400 MHz, cdcl3) δ 7.68 - 7.62 (m, 1 H), 7.59 - 7.45 (m, 3H), 7.33 - 7.28 (m, 1 H), 7.15 - 7.10 (m, 1 H), 6.41 - 6.32 (m, 1 H), 4.49 (q, J = 6.9 Hz, 1 H), 2.50 (s, 3H), 2.16 (d, J = 7.0 Hz, 3H).

PREPARATION 26 15 Methyl 1-(phenylsulfonyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate

a) Methyl 3-iodo-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate

20 [0197] A solution of methyl 3-bromo-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate2 (2,0 g, 5,8 mmol), sodium iodide (3,5 g, 23 mmol), trans-1,2-bis(methylamino)cyclohexane (0,83 g, 5,84 mmol) and copper iodide (0,55 g, 2,9 mmol) in 1,4-dioxane (23 mL) was stirred under reflux during 3 days. At the end of this period, the crude was allowed to reach room temperature and filtered thought Celite® washing with ethyl acetate. The filtrate was concentrated to dryness, suspended in 80 mL of HCl 1N and extracted with ethyl acetate (3x). The organic mixture was washed with water and 25 brine, dried (Mg 2SO4) and concentrated to give an oily residue that was purified by flash chromatography silica (hexane/ ethyl acetate). Concentration of the fractions containing the compound afforded 1,72 g (50%) of the title compound. LRMS (m/z): 392 (M+1)+.

b) Methyl 1-(phenylsulfonyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 30 [0198] In a schlenk flask were placed methyl 3-iodo-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (2,44 g, 6,24 mmol) and copper iodide (1,46 g, 7,7 mmol) and it was established an inert atmosphere doing 3 cycles of vacuum-Ar. Subse- quently, were added dimethyl formamide (44 mL) as solvent, hexamethylphosphoramide (HMPA) (5,4 mL, 31 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3,9 mL, 30,7 mmol) and the reaction mixture was heated to 80TC 35 during 24 hous. Having consumend the starting material, the crude was poured into abundant ice-water an extracted with ethyl acetate (3x). The organic mixture was washed with water (2x) and brine, dried (Na2SO4) and concentrated in vacuo to give 2,58 g of a residue that was purified by flash chromatography silica (hexane/ ethyl ether). Concentration of the fractions containing the compound afforded 370 mg (18%) of the title compound. LRMS (m/z): 334 (M+1)+. 40 1 H NMR (400 MHz, CDCl3) δ 8.07 - 7.99 (m, 2H), 7.69 (m, 1 H), 7.62 - 7.55 (m, 2H), 7.48 (d, J = 3.4 Hz, 1 H), 6.51 (d, J = 3.4 Hz, 1 H), 3.91 (s, 3H).

PREPARATION 27

45 1-Amino-N-o-tolyl-3-(trifluoromethyl)-1H-pyrrole-2-carboxamide

a) 1-(Phenylsulfonyl)-N-o-tolyl-3-(trifluoromethyl)-1H-pyrrole-2-carboxamide

[0199] In a three-necked round-bottom flask o-toluidine (0,53 g, 5 mmol) was dissolved in 15 mL of toluene under 50 inert atmosphere. To this solution was added trimethy aluminium (2,5 mL, 5 mmol) and the mixture was stirred at room temperature during 10 minutes. Afterwards, a solution of methyl 1-(phenylsulfonyl)-3-(trifluoromethyl)-1 H-pyrrole-2-carboxylate (207 mg, 0,62 mmol) in 15 mL of toluene were added and the reaction mixtures was heated at 80 TC over night. Next, the mixtured was allowed to cool to room temperature and 2-3 mL of water were added to hydrolize unreacted trimethyl aluminium and a 0,5M aqueous solution of disodium tartrate dihidrate were added stirring for a while. Afterwards, 55 the two layers were separated and the aqueous phase was extracted with ethyl acetate. The organic mixture was washed with the same 0,5M aqueous solution of disodium tartrate dihidrate (25 mL), water and brine, dried and concentrated in vacuo to afford 560 mg of a residue that was used in the following step without further purification. LRMS (m/z): 409 (M+1)+.

49 EP 2 518 070 A1

b) N-o-tolyl-3-(trifluoromethyl)-1H-pyrrole-2-carboxamide

[0200] To a solution of 1-(phenylsulfonyl)-N-o-tolyl-3-(trifluoromethyl)-1H-pyrrole-2-carboxamide (560 mg of crude material) in 12 mL of methanol was added 2 mL of an aqueous 1 N solution of sodium hydroxide and the mixture was 5 stirred atroom temperatureduring 1 h. At the end of this period, no starting material was detected and the reaction was elaborated in the following way: methanol was evaporated and water was added basifying the mixture with saturated aqueous solution of potassium carbonate. This mixture was extracted with ethyl acetate and this organic phase was washed with water and brine, dried (Na 2SO4) and concentrated to dryness affording a reddish residue. This residue was purified by flash chromatography silica (hexane/ethyl ether). Concentration of the fractions containing the compound 10 afforded 120 mg (50%) of the title compound. LRMS (m/z): 269 (M+1)+.

c) 1-Amino-N-o-tolyl-3-(trifluoromethyl)-1H-pyrrole-2-carboxamide

15 [0201] This compound was prepared starting from N-o-tolyl-3-(trifluoromethyl)-1H-pyrrole-2-carboxamide (120 mg, 0,35 mmol) and following the experimental procedure described in Preparation 1b to afford 44 mg (31% purity, 14% yield) of the title compound that was used in the next step without any further purification. LRMS (m/z): 284 (M+1)+.

20 PREPARATION 28

2-(Chloromethyl)-3-o-tolyl-5-(trifluoromethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0202] This compound was prepared starting from 1-amino-N-o-tolyl-3-(trifluoromethyl)-1H-pyrrole-2-carboxamide 25 (44 mg, 31 % purity, 0,05 mmol) and following the experimental procedure described in Preparation 1 c to afford 2 mg (67% purity, 8% yield) of the title compound that was used in the following step without further purification. LRMS (m/z): 342 (M+1)+.

PREPARATION 29 30 1-Amino-3-chloro-1H-pyrrole-2-carboxylic acid

a) Benzyl 3-chloro-1H-pyrrole-2-carboxylate

35 [0203] To a solution of 3-chloro-1H-pyrrole-2-carboxylic acid (15 g, 0,1 mol) in N,N-dimethylformamide (300 mL) and triethylamine (72 mL, 0,52 mmol) under argon atmosphere was added benzyl bromide (61 mL, 0,52 mmol) at 0-5TC and the reaction was stirred mechanically overnight at room temperature. Next day, the reaction mixture was concentrated in vacuo and the residue was suspended in 4% aqueous solution of sodium bicarbonate (300 mL) and extracted with ethyl acetate (2x250 mL). The organic layers were mixed and washed with more 4% aqueous solution of sodium bicar- 40 bonate, water and brine, and were dried (magnesium sulphate, MgSO4) and concentrated under reduced presure to give 21,4 g of a residue corresponding to the title compound (88% yield). LRMS (m/z): 236 (M+1)+.

b) Benzyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate 45 [0204] This compound was prepared starting from benzyl 3-chloro-1H-pyrrole-2-carboxylate (21,3 g, 0,09 mol) and following the experimental procedure described in Preparation 1 b to afford 22,19 g (92% yield) of the title compound that was used in the next step without any further purification. LRMS (m/z): 251 (M+1)+. 50 c) 1-Amino-3-chloro-1H-pyrrole-2-carboxylic acid

[0205] To a solution of benzyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (20,56 g, 0,08 mol) in methanol (205 mL) was added 32,1 mL of a 3M methanolic solution of HCl (0,1 mol) and 7,7 g (0,07 mol) of 10% palladium on charcoal 55 and this mixture was submitted to hydrogenation in a Parr apparatous working at 25 psi and room temperature during 21 hours. At the end of this period, the reaction was stopped filtering palladium catalyst throught a pad of Celite® and the filtrate was concentrated in vacuo to give a light brown solid that was macerated with 40 mL of diethyl ether. This solid was filtrated and washed with petroleoum ether to yield 13,32 g of the title compound with a purity of 55% (59%

50 EP 2 518 070 A1

yield) being the dehalogenated compound the main impurity. No further purifications were done proceding to the next step. LRMS (m/z): 159 (M-1)-. 1H NMR (400 MHz, dmso) δ 7.51 (s, 2H), 7.05 (d, J = 2.9 Hz, 1 H), 6.10 (d, J = 2.9 Hz, 1 H).

5 PREPARATION 30

5-Chloro-2-(iodomethyl)-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-4-one

a) 3-Chloro-1-(2-chloroacetamido)-1H-pyrrole-2-carboxylic acid 10 [0206] To a solution of 1-amino-3-chloro-1H-pyrrole-2-carboxylic acid (12,51 g, 55% purity, 0,04 mol) in 500 mL of glacial acetic acid were added under argon 17 mL of chloroacetyl chloride (0,21 mol) and the mixture was stirred at room temperature during 1,5 hours. Afterwards, the reaction mixture was poured into ice-water and extracted with ethyl acetate (2x400 mL). The organic layers were washed with water and brine, dried (MgSO 4) and concentrated in vacumm giving 15 a dark oil that was crystallized from a 1/1 diethyl ether/ petroleoum ether mixture. Filtration of the solid obtained afforded 7,28 g of a white solid corresponding to the title compound (61 % yield, 85% purity). This solid was used in the next step without further purifications. LRMS (m/z): 237 (M+1)+.

20 b) 5-Chloro-2-(chloromethyl)-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-4-one

[0207] To a solution of 3-chloro-1-(2-chloroacetamido)-1H-pyrrole-2-carboxylic acid (7,22 g, 25,9 mmol) in 110 mL of 1,4-dioxane was added phophorous oxychloride (23,6 mL, 259mmol) solved in 35 mL of 1,4- dioxane at room temperature. Then, the reaction mixture was stirred to reflux during 2 hours. At the end of this period, the reaction mixture was poured 25 into 500 mL of a 4% aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2x400 mL). The organic layers were mixed and washed with more 4% aqueous solution of sodium bicarbonate, water and brine, and were dried (MgSO4) and concentrated under reduced presure to give 6,97 g of a dark oil that was purified by flash chromatography silica (hexane/ethyl acetate). After purification were obtained 2,85 g of the title compound (57% yield). LRMS (m/z): 219 (M+1)+. 30 c) 5-Chloro-2-(iodomethyl)-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-4-one

[0208] To a solution of 5-chloro-2-(chloromethyl)-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-4-one (2,87 g, 13,1 mmol) in 57 mL of dry acetone under inert atmosphere was added 3,93 g (26,2 mmol) of sodium iodide and this mixture was stirred 35 at room temperature overnight. Next day, the reaction mixture was poured into a 1/1 mixture of water/brine (100 mL) and extracted with diethyl ether (2x 75 mL). The organic layers were washed with water and brine, dried (MgSO4) and concentrated in vacuo to afford 3,95 g of the title compound (95% yield). LRMS (m/z): 311 (M+1)+. 1 H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 3.0 Hz, 1 H), 6.52 (d, J = 3.0 Hz, 1 H), 4.10 (s, 2H). 40 PREPARATION 31

Di-tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)me-thyl)-9H-purin-6-ylimidodicarbonate

45 [0209] To a solution of 5-chloro-2-(iodomethyl)-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-4-one (0,93 g, 3 mmol) in 18,6 mL of dry N,N-dimethylformamide under argon atmosphere were added di-tert-butyl 9H-purin-6-ylimidodicarbonate (1,41 g, 4,2 mmol) and sodium bicarbonate (0,35 g, 4,2 mmol) and the reaction mixture was stirred overnight at room temperature. At the end of this period, the reaction mixture was poured into 50 mL of a 4% aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2x40 mL). The organic layers were mixed and washed with more 4% 50 aqueous solution of sodium bicarbonate, water and brine, and were dried (MgSO4) and concentrated under reduced presure to give 1,73 g of a solid that was was purified by flash chromatography silica (hexane/ethyl acetate). After purification were obtained 0,81 g of the title compound (51% yield). LRMS (m/z): 517 (M+1)+. 1 H NMR (400 MHz, CDCl 3) δ 8.89 (s, 1 H), 8.23 (s, 1 H), 7.16 (d, J = 3.0 Hz, 1 H), 6.49 (d, J = 3.0 Hz, 1 H), 5.37 (s, 2H), 55 1.48 (s, 18H).

51 EP 2 518 070 A1

PREPARATION 32

1H-imidazole-2-carboxylic acid

5 [0210] 21.75 mL (43.5 mmol) of a 2M solution of lithium hydroxide in water were added to a solution of 1.22 g (8.71 mmol) of ethyl 1 H-imidazole-2-carboxylate (ref) in a mixture of tetrahydrofurane (20 mL) and water (20 mL). The reaction mixture was warmed up to reflux, and stirred for 1.5 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under vacuum. The crude residue (3.0 g) was used in next step without further purification. LRMS (m/z): 113 (M+1)+. 10 PREPARATION 33

1-amino-N-phenyl-1H-imidazole-2-carboxamide

15 a) N-phenyl-1H-imidazole-2-carboxamide

[0211] To a solution of 1H-imidazole-2-carboxylic acid (0.975 g, 8.7 mmol) in DMF (30 mL) were added aniline (0.67 mL, 8.7 mmol), EDC·HCl (2.54 g, 13.05 mmol) and HOBt (1.76 g, 13.05 mmol). The reaction mixture was stirred at room temperature for 21 hours. Then, it was poured into water and extracted with ethyl acetate. The combined organic layer 20 was dried over sodium sulphate, filtered and concentrated. The crude residue was purified by flash chromatography (2% to 3% methanol in dichloromethane) to yield 1.55 g (96% yield) of the title compound. LRMS (m/z): 188 (M+1)+.

b) 1-amino-N-phenyl-1H-imidazole-2-carboxamide 25 [0212] 0.430 g (10.75 mmol) of sodium hydride (60 % dispersion in mineral oil) were added to a 0 TC cooled solution of N-phenyl-1H-imidazole-2-carboxamide (1.55 g, 8.27 mmol) in DMF (50 mL). The mixture was stirred at 0 TC for 30 ® minutes and 2.70 g (11.57 mmol) of DPPONH 2 (P,P-diphenylphosphinic amide, available from Sigma Aldrich , cat. no. 5994-87-6) were added portionwise. A thick suspension formed and additional 100 mL of DMF were added. The mixture 30 was stirred at room temperature for 3 hours and then it was poured into 150 mL of a saturated aqueous solution of sodium thiosulphate and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography (20% to 40% EtOAc/Hexanes) to yield 1.27 g (76% yield) of the title compound as a pale yellow solid. LRMS (m/z): 203 (M+1)+. 35 PREPARATION 34

2-(chloromethyl)-3-phenylimidazo[1,2-f][1,2,4]triazin-4(3H)-one62 mg (0.25 mmol) of pyridinium p-toluenesulfonate were added to a suspension of 500 mg (2.47 mmol) of 1-amino-N-phenyl-1H-imidazole-2-carboxamide in 3.3 mL of 40 2-chloro-1,1,1-trimethoxyethane. The mixture was stirred at 100 TC for 5 hours and the solvent was evaporated. The crude product was purified by flash chromatography (1% to 3% MeOH/DCM) to yield 0.227 g (35%) of the title compound as a beige solid.

[0213] LRMS (m/z): 261 (M+1)+. 45 PREPARATION 35

1-amino-N-o-tolyl-1H-imidazole-2-carboxamide

50 a) N-o-tolyl-1H-imidazole-2-carboxamide

[0214] To a solution of 1H-imidazole-2-carboxylic acid (0.52 g, 4.64 mmol) in DMF (20 mL) was addedo -toluidine (0.50 mL, 4.64 mmol), EDC·HCl (1.35 g, 6.96 mmol) and HOBt (0.94 g, 6.96 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, it was poured into water and extracted with ethyl acetate. The combined organic 55 layer was dried over sodium sulphate, filtered and concentrated to dryness. The crude product was purified by flash chromatography (2% to 3% MeOH/DCM) to yield 0.93 g (99%) of the title compound as a beige solid. LRMS (m/z): 202 (M+1)+.

52 EP 2 518 070 A1

b) 1-amino-N-o-tolyl-1H-imidazole-2-carboxamide

[0215] 240 mg (6.02 mmol) of sodium hydride (60% dispersion in mineral oil) were added to a 0T C cooled solution of N-o-tolyl-1H-imidazole-2-carboxamide (0.93 g, 4.63 mmol) in DMF (120 mL). The mixture was stirred at 0 TC for 30 5 ® minutes and DPPONH2 (1.51 g, 6.49 mmol, available from Sigma Aldrich , cat. no. 5994-87-6) was added portionwise. The mixture was stirred at room temperature for 2 hours and then it was poured into 200 mL of a saturated aqueous solution of sodium thiosulphate and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography (20% to 50% EtOAc/ Hexanes) to yield 0.55 g (55%) of the title compound as a beige solid. 10 LRMS (m/z): 217 (M+1)+.

PREPARATION 36

2-(chloromethyl)-3-o-tolylimidazo[1,2-f][1,2,4]triazin-4(3H)-one 15 [0216] Pyridinium p-toluenesulfonate (0.067 g, 0.27 mmol) was added to a suspension of 1-amino-N-o-tolyl-1H-imidazole-2-carboxamide (0.58 g, 2.68 mmol) in 2- chloro-1,1,1-trimethoxyethane (3.62 mL). The mixture was stirred at 100 TC for 5 hours. The solvent was evaporated to dryness and the residue was purified by flash chromatography (10% to 50% AcOEt/hexanes) to yield 0.360 g (49% yield) of the title compound. 20 LRMS (m/z): 275 (M+1)+.

PREPARATION 37

1-Amino-N-(3-fluorophenyl)-1H-pyrrole-2-carboxamide 25 [0217] This compound was prepared starting from 1 H-pyrrole-2-carboxylic acid (0,67 g, 6 mmol) and following the experimental procedure described in Preparation 1 to afford 0,525 g (39% yield) of the title compound that was used in the next step without any further purification. LRMS (m/z): 220 (M+1)+. 30 PREPARATION 38

1-Amino-N-(3,5-difluorophenyl)-1H-pyrrole-2-carboxamide

35 [0218] This compound was prepared starting from 1H-pyrrole-2-carboxylic acid (0,67 g, 6 mmol) and following the experimental procedure described in Preparation 1 to afford 0,393 g (26% yield) of the title compound that was used in the next step without any further purification. LRMS (m/z): 238 (M+1)+.

40 PREPARATION 39

(S)-2-(1-Aminoethyl)-3-(3-fluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0219] This compound was prepared starting from 1-amino-N-(3-fluorophenyl)-1H-pyrrole-2-carboxamide (525 mg, 45 2,39 mmol) and following the experimental procedure described in Preparation 22 to afford 42 mg (7% yield) of the title compound. LRMS (m/z): 273 (M+1)+.

PREPARATION 40 50 (S)-2-(1-Aminoethyl)-3-(3,5-difluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0220] This compound was prepared starting from 1-Amino-N-(3,5-difiuorophenyl)-1H-pyrrole-2-carboxamide (393 mg, 1,66 mmol) and following the experimental procedure described in Preparation 22 to afford 36 mg (7% yield) of the 55 title compound. LRMS (m/z): 291 (M+1)+.

53 EP 2 518 070 A1

PREPARATION 41

1-Amino-N-(pyridin-2-yl)-1H-pyrrole-2-carboxamide

5 [0221] This compound was prepared starting from 1H-pyrrole-2-carboxylic acid (2 g, 18 mmol) and 2-aminopyridine (3,40 g, 36 mmol), following the experimental procedure described in Preparation 1 to afford 0,34 g (9% yield) of the title compound that was used in the next step without any further purification. LRMS (m/z): 203 (M+1)+.

10 PREPARATION 42

(S)-2-(1-Aminoethyl)-3-(pyridin-2-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one dihydrochloride

a) (S)-tert-Butyl 1-oxo-1-(2-(pyridin-2-ylcarbamoyl)-1H-pyrrol-1-ylamino)propan-2-ylcarbamate 15 [0222] This compound was prepared starting from 1- amino-N-(pyridin-2-yl)-1H-pyrrole-2-carboxamide (340 mg, 1,68 mmol) and following the experimental procedure described in Preparation 22a to afford 440 mg (56% yield) of the title compound of preparation 42a.

20 b) (S)-2-(1-Aminoethyl)-3-(pyridin-2-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one dihydrochloride

[0223] A solution of bromine (113 PL, 2,21 mmol) in dichloromethane (2 mL) was added dropwise to a solution of triphenylphosphine (558 mg, 2,13 mmol) in dichloromethane (5 mL) under nitrogen. The solution was stirred for 30 min, and triethylamine (494 PL, 3,51 mmol) and a solution of (S)-tert-butyl 1-oxo-1-(2-(pyridin-2-ylcarbamoyl)-1H-pyrrol-1- 25 ylamino)propan-2-ylcarbamate (440 mg, 0,94 mmol) in 3 ml of dichlloromethane were added. The reaction mixture was stirred at room temperature for 3,5 h, and then, volatiles were removed under reduced pressure and the residue was triturated with toluene affording a solid that was removed by filtration. The filtrate was concentrated to dryness under reduced pressure and the residue was redissolved in 20 mL of a 7M methanolic solution of ammonia and stirred overnight at 80 TC in a sealed vessel. The solvent was then evaporated and the residue was purified by flash chromatography 30 (0% to 50% AcOEt/ hexanes) to yield 0.19 g (57% yield) of (S)-tert- butyl 1-(4-oxo-3-(pyridin-2-yl)-3,4-dihydropyrrolo[1,2- f][1,2,4]triazin-2-yl)ethylcarbamate. This compound (190 mg, 0,43 mmol) was disolved in 2 ml of dioxane and 2 ml of a 4M hydrogen chloride solution in dioxane were added. The mixture was stirred at room temperature overnight. Then, the solid present in the reaction media was filtered-off and washed with hexane to afford 127 mg of the title compound of preparation 42 (90% yield). 35 LRMS (m/z): 256 (M+1)+.

PREPARATION 43

(S)-3-Phenyl-2-(pyrrolidin-2-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one 40 a) (S)-Tert-butyl 2-(2-(phenylcarbamoyl)-1H-pyrrol-1-ylcarbamoyl)pyrrolidine-1-carboxylate

[0224] (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.80 g, 8.36 mmol) were dissolved in 20 ml N of, N-dimethylformamide and HATU (3.40 g, 8.95 mmol), DIEA (2.60 ml, 14.89 mmol) and 1-amino-N-phenyl-1H-pyrrole- 45 2-carboxamide were added. The resulting solution was stirred at room temperature overnight and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and evaporated to dryness. The crude product was purified by flash chromatography (0% to 30% hexane/AcOEt) to yield 1.90 g (62%) of the title compound as a white solid. LRMS (m/z): 399 (M+1)+. 50 b) (S)-Tert butyl 2-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidine-1-carboxylate

[0225] To a solution of 2.50 g (9.54 mmol) of triphenylphosphine in 20 ml of methylene chloride was added a solution of 1.52 g (9.54 mmol) of bromine in 10 ml of dichloromethane dropwise under nitrogen atmosphere. At the end of the 55 addition the colorless solution was stirred for 5 minutes and then 3.32 ml (23.84 mmol) of triethylamine and 1.90 g (4.77 mmol) of (S)-Tert-butyl 2-(2-(phenylcarbamoyl)-1H-pyrrol-1-ylcarbamoyl)pyrrolidine-1-carboxylate were added. The reaction mixture was then stirred at reflux for 3 hours and then cooled and the solvent was evaporated. The residue was taken up in cold toluene and the insoluble salts were filtered. The filtrate was evaporated and the residue was then

54 EP 2 518 070 A1

redissolved in a mixture of tetrahydrofurane (30 ml) and methanol (10 ml) and 1.00 g (14.31 mmol) of sodium methanethiolate was added. The solution was stirred at 60 TC for 3 hours. Then the solvents were evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under vacuo. The product was purified by flash chromatography (20% to 5 40% hexane/AcOEt) to yield 1.20 g (66%) of the title compound. LRMS (m/z): 381 (M+1)+.

c) (S)-3-Phenyl-2-(pyrrolidin-2-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

10 [0226] 1.20 g (3.16 mmol) of (S)-Tert-butyl 2-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidine- 1-carboxylate were dissolved in 2 ml of methylene chloride and 2 ml of trifluoroacetic acid were added. The resulting solution was stirred at room temperature for 1 hour and the reaction mixture was evaporated to dryness. The residue was then redissolved in dichloromethane and the solution was washed with an aqueous solution of sodium bicarbonate and brine, dried over magnesium sulphate, filtered and the solvent was removed under vacuo to yield 0.80 g (91 %) of 15 the title compound. LRMS (m/z): 281 (M+1)+. 1H NMR (400 MHz, DMSO-d6) δ δ 7.56 (dd, 1H), 7.55 - 7.42 (m, 4H), 7.41 - 7.37 (m, 1 H), 6.93 (dd, 1 H), 6.57 (dd, 1 H), 3.14- 2.97(m, 1 H), 2.39(dd, 2H), 2.07- 1.93(m, 1 H), 2.00(s, 1H), 1.91 - 1.78(m, 1H), 1.69 (tt, 1H), 1.60 - 1.49 (m, 1H).

20 EXAMPLE 1

2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0227] A mixture of 5-chloro-2-(chloromethyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (90 mg, 0,25 mmol) and 25 adenine (43 mg, 0,32 mmol) was suspended in /V,/V- dimethylformamide (2 mL) and potassium carbonate (44 mg, 0,32 mmol) was added stirring the reaction at room temperature overnight. At the end of this period, dichloromethane was added and the insolubles were filtered out. The filtrate was concentrated to dryness and macerated with dimethylsul- phoxyde affording 57 mg (51 % yield) of a solid corresponding to the title compound. LRMS (m/z): 407 (M+1)+. 30 1H NMR (400 MHz, dmso) δ 8.06 (s, 1 H), 7.92 (s, 1 H), 7.61 (d, J = 3.0 Hz, 1 H), 7.54 - 7.33 (m, 4H), 7.25 (s, 2H), 6.67 (d, J = 3.0 Hz, 1 H), 5.03 (d, J = 17.1 Hz, 1 H), 4.79 (d, J = 17.1 Hz, 1 H), 2.11 (s, 3H).

EXAMPLE 2

35 2-((6-Aminopyrimidin-4-ylamino)methyl)-5-chloro-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0228] In a microwave tub, a mixture of 2-(aminomethyl)-5-chloro-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (85 mg, 0,29 mmol), 6-bromopyrimidin-4-amine (102 mg, 0,59 mmol), and DIEA (205 PL, 1,2 mmol) was dissolved in tert- butanol (3 mL) and was heated at 140 TC with stirring during 20 hours. Next day, ethyl acetate was added and the organic 40 phase was washed with water and brine, dried (Na 2SO4) and concentrated to give 180 mg of a residue that was purified using a bond elut 5g silica cartridge eluting with dichloromethane/methanol mixtures obtain 5 mg of the title compound (4% yield). LRMS (m/z): 382 (M+1)+.

45 EXAMPLE 3

2-((6-Amino-9H-purin-9-yl)methyl)-5-cyclopropyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0229] This compound was prepared starting from 2-(chloromethyl)-5-cyclopropyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin- 50 4(3H)-one (107 mg, 0,29 mmol) and following the experimental procedure described in Example 1. Isolation of the compound was done by reverse phase chromatography (C-18 silica from Waters, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to afford 12 mg (10% yield) of the title compound. LRMS (m/z): 413 (M+1)+. 1H NMR (400 MHz, dmso) δ 8.05 (s, 1 H), 7.47-7.38 (m, 5H), 7.22 (s, 2H), 6.14 (d, J = 2.8 Hz, 1 H), 5.01 (d, J = 16.9 55 Hz, 1 H), 4.78 (d, J = 16.9 Hz, 1 H), 2.50 (m, 1 H), 2.10 (s, 3H), 0.94 (d, J = 8.6 Hz, 2H), 0.70 - 0.56 (m, 2H).

55 EP 2 518 070 A1

EXAMPLE 4

2-((6-amino-9H-purin-9-yl)methyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

5 [0230] To a solution of 2-(chloromethyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (90 mg, 0,23 mmol) in dryN , N-dimethylformamide (4 mL), 9H-purin-6-amine (38 mg, 0,28 mmol) and potasium carbonate (38 mg, 0,27 mmol) were added. It was stirred at room temperature overnight. It was filtered through Celite® and it was concentrated in vacuo. The residue obtained was purified by flash chromatography silica (dichloromethane/methanol). The expected product was obtained (25 mg, 29% yield). 10 LRMS (m/z): 373 (M+1)+. 1H NMR (400 MHz, dmso) δ 8.06 (s, 1 H), 7.92 (s, 1 H), 7.53 - 7.62 (m, 1 H), 7.50 (d, J=7.42 Hz, 1 H), 7.34 - 7.48 (m, 3 H), 7.25 (s, 2 H), 7.00 (dd, J=4.30, 1.56 Hz, 1 H), 6.58 (dd, J=4.30, 2.74 Hz, 1 H), 5.07 (d, J=16.80 Hz, 1 H), 4.82 (d, J=16.80 Hz, 1 H), 2.09 (s, 3 H).

15 EXAMPLE 5

2-((6-aminopyrimidin-4-ylamino)methyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0231] 100 mg (0.39 mmol) of 2-(aminomethyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 76 mg (0.44 mmol) of 20 6-bromopyrimidin-4-amine and 140 PL (0.80 mmol) of DIEA were suspended in 2 mL of tert-butanol and the resulting mixture was stirred at 80 TC overnight. After an extra addition of 76 mg (0.44 mmol) of 6-bromopyrimidin-4-amine and 140 PL (0.80 mmol) of DIEA the reaction was heated at 80 TC for 70 hours. Then the solvents were evaporated under vacuum and the crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1 % v/v formic acid buffered] 0% to 100%) and then by preparative HPLC (Symmetry 25 Prep C18 column, mixture of eluents A/B from 20% B to 20% B, in a 10 min. gradient) to give 18 mg (13% yield) of the title compound. LRMS (m/z): 348 (M+1)+.

EXAMPLE 6 30 4-((4-Oxo-3-o-tolyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)methylamino)picolinamide

[0232] A mixture of 2-(aminomethyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (102 mg, 04 mmol), 4-bromopicol- inamide (105 mg, 0,52 mmol) and DIEA (200P L, 1,13 mmol) in n-butanol (2,2 mL) was reacted under microwave 35 irradiation at 190TC during 22 h. After cooled to room temperature, the mixture was concentrated in vacuo and was purified by reverse phase chromatography (C-18 silica from Waters, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain 7 mg of the title compound (4,6%). LRMS (m/z): 375 (M+1)+. 1H NMR (400 MHz, dmso) δ 8.38 (s, 2 H), 8.01 (d, J=5.86 Hz, 1 H), 7.90 (m, 1 H), 7.61 - 7.73 (m, 1 H), 7.48 - 7.58 (m, 40 1 H), 7.39 - 7.48 (m, 1 H), 7.23 - 7.40 (m, 2 H), 7.03 - 7.14 (m, 1 H), 6.93 - 7.04 (m, 1 H), 6.62 (dd, J=4.30, 2.74 Hz, 1 H), 6.38 - 6.53 (m, 1 H), 3.86 - 3.99 (m, 2 H), 2.08 (s, 3 H)

EXAMPLE 7

45 2-((2-aminopyridin-4-ylamino)methyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0233] 150 mg (0.59 mmol) of 2-(aminomethyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 104 mg (0.60 mmol) of 4-bromopyridin-2-amine and 105 PL (0.60 mmol) DIEA were dissolved in 2 mL oftert -butanol and stirred at 180 TC under microwave irradiation for 5.5 hours. Then the solvent was evaporated in vacuo and the crude product was purified 50 by flash chromatography (dichloromethane to dichloromethane/MeOH/NH40H, 100:8:1) to give 57 mg (28% yield) of the title compound. LRMS (m/z): 347 (M+1)+. 1H NMR (400 MHz, DMSO) δ 7.69 (s, 1 H), 7.55 - 7.29 (m, 5H), 6.99 (s, 1 H), 6.62 (s, 1 H), 6.37 (s, 1 H), 5.76 (s, 1 H), 5.54 (s, 2H), 5.40 (s, 1 H), 3.85 - 3.66 (m, 2H), 2.08 (s, 3H). 55

56 EP 2 518 070 A1

EXAMPLE 8

2-((9H-purin-6-ylamino)methyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

5 [0234] 100 mg (0.39 mmol) of 2-(aminomethyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 86 mg (0.43 mmol) of 6-bromo-9H-purine and 151 PL (0.87 mmol) DIEA were dissolved in 5 mL of tert- butanol and stirred at 80 TC overnight. Then the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and brine. It was dried over magnesium sulphate, filtered and the solvent was evaporated. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 10 acetonitrile-methanol as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to give 42 mg (29% yield) of the title compound. LRMS (m/z): 373 (M+1)+. 1 H NMR (400 MHz, DMSO) δ 12.95 (s, 1 H), 8.14 (s, 1 H), 8.08 (s, 1 H), 7.87 (s, 1 H), 7.62 (s, 1 H), 7.46 (d, J = 7.1 Hz, 1 H), 7.42 - 7.22 (m, 3H), 6.97 (dd, J = 4.3, 1.6 Hz, 1 H), 6.57 (dd, J = 4.3, 2.7 Hz, 1 H), 4.20 (bs, 2H), 2.19 (s, 3H). 15 EXAMPLE 9

2-((6-Amino-9H-purin-9-yl)methyl)-3-cyclohexylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

20 [0235] The compound of Preparation 11 (140 mg, 0,53 mmol), 9H-purin-6-amine (91 mg, 0,67 mmol) and potassium carbonate (93 mg, 0,67 mmol) were suspended in /V,/V-dimethylformamide under argon atmosphere and the reaction was stirred overnight at room temperature. Next day, dichloromethane was added and the resulting solid was filtered off. The filtrate was concentrated to dryness giving a residue of 176 mg that was purified by flash chromatography silica (dichloromethane/methanol) to obtain 7 mg of the title compound (3,4% yield). 25 LRMS (m/z): 365 (M+1)+. 1H NMR (400 MHz, dmso) δ 8.19 (s, 1 H), 8.21 (s, 1 H), 7.46 (brs, 1 H), 7.32 (brs, 2H), 6.90 - 6.77 (m, 1 H), 6.57 - 6.47 (m, 1 H), 5.58 (s, 2H), 3.86 (s, 1 H), 1.63 - 0.96 (m, 10H).

EXAMPLE 10 30 2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0236] 50 mg (0.17 mmol) of 2-(chloromethyl)-5-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 25.8 mg (0.19 mmol) of 9H-purin-6-amine and 26.4 mg of potassium carbonate were dissolved in 2.5 mL of DMF and stirred at room 35 temperature for 3 hours. Then the reaction mixture was diluted with dichloromethane, filtered and evaporated to dryness. The oil that resulted was purified by flash chromatography (DCM to 5% MeOH/DCM) to give 52 mg (77% yield) of the title compound. LRMS (m/z): 387 (M+1)+.

40 EXAMPLE 11

2-((9H-purin-6-ylthio)methyl)-5-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0237] To a solution of 2-(chloromethyl)-5-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (108 mg, 0,38 mmol) 45 in 7,5 mL of N,N-dimethylformamide was added 9 H-purine-6-thiol (57 mg, 0,37 mmol) and potassium carbonate (52 mg, 0,38 mmol) and the stirring was continued overnight at room temprerature. Next day, the reaction was concentrated to dryness and the residue was purified by reverse phase chromatography (C-18 silica from Waters, water/ 1:1 acetonitrile- methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain 35 mg of the title compound (23%). LRMS (m/z): 404 (M+1)+. 50 1H NMR (400 MHz, dmso) δ 8.46 (s, 1 H), 8.39 (s, 1 H), 7.53 (d, J = 2.7 Hz, 1 H), 7.44 (m, 1 H), 7.24 (m, 3H), 6.42 (d, J = 2.7 Hz, 1H), 4.38 (d, J = 15.2 Hz, 1 H), 4.26 (d, J = 15.2 Hz, 1 H), 2.39 (s, 3H), 2.15 (s, 3H).

EXAMPLE 12

55 2-((6-amino-9H-purin-9-yl)methyl)-6-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0238] 289 mg (1.00 mmol) of 2-(chloromethyl)-6-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 163 mg (1.21 mmol) of 9H-purin-6-amine and 278 mg (2.01 mmol) of potassium carbonate were dissolved in 8 mL of DMF and stirred

57 EP 2 518 070 A1

at room temperature overnight. The solvent was removed in vacuo and the residue was taken up in ethyl acetate, washed with brine, filtered and evaporated to dryness. The product was purified by preparative HPLC (Symmetry Prep18 C column, mixture of eluents A/B from 40% B to 52% B, in a 12 min. gradient) to give 116 mg (29% yield) of the title compound. LRMS (m/z): 387 (M+1)+. 5 1 H NMR (400 MHz, DMSO) δ 8.04 (s, 1 H), 7.88 (s, 1 H), 7.52 - 7.29 (m, 5H), 7.24 (s, 2H), 6.80 (s, 1 H), 5.04 (d, J = 17.0 Hz, 1 H), 4.80 (d, J = 16.9 Hz, 1 H), 2.13 (s, 3H), 2.04 (s, 3H).

EXAMPLE 13

10 2-((9H-purin-6-ylthio)methyl)-6-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0239] 289 mg (1.00 mmol) of 2-(chloromethyl)-6-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 183 mg (1.21 mmol) of 7H-purine-6-thiol and 277 mg (2.01 mmol) of potassium carbonate were dissolved in 8 mL of DMF and stirred at room temperature overnight. The solvent was removed in vacuo and the product was purified by preparative HPLC 15 (Symmetry Prep C18 column, mixture of eluents A/B from 50% B to 63% B, in a 13 min. gradient) to give 133 mg (50% yield) of the title compound. LRMS (m/z): 404 (M+1)+. 1 H NMR (400 MHz, DMSO) δ 8.47 (s, 1 H), 8.43 (s, 1 H), 7.51 - 7.16 (m, 5H), 6.79 (s, 1 H), 4.41 (d, J = 15.2 Hz, 1 H), 4.29 (d, J = 15.2 Hz, 1 H), 2.16 (s, 3H), 2.11 (s, 3H).

20 EXAMPLE 14

2-(1-(6-amino-9H-purin-9-yl)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0240] To a solution of 100 mg (0.37 mmol) of 2-(1- chloroethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one in 5 mL 25 of DMF, 55 mg (0.41 mmol) of 9H-purin-6-amine and 55 mg (0.40 mmol) of potassium carbonate were added. It was stirred at 60 TC overnight. It was then filtered through Celite® and it was concentrated in vacuo. The residue that was obtained was purified by flash chromatography (5% MeOH in dichloromethane). 20 mg (15% yield) of the title product were obtained. LRMS (m/z): 373 (M+1)+. 30 1 H NMR (400 MHz, DMSO) δ ppm 8.27 - 7.80 (m, 2H), 7.82 - 6.88 (d, J = 7.03 Hz, 1 H), 6.64 (m, 1 H), 5.49 (q, J = 6.25 Hz, 1 H), 1.71 (d, J = 5.86 Hz, 3H).

EXAMPLE 15

35 (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0241] 90 mg (0.34 mmol) of ( S)-2-(1-aminopropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 134 mg (0.67 mmol) of 6-bromo-9H-purine and 174 mg (1.35 mmol) of DIEA were suspended in 3 mL of tert-butanol and the mixture was heated to 100 TC for 40 hours. Then the solvent was removed in vacuo and the residue was taken up in AcOEt, washed 40 with water and brine, dried over magnesium sulphate and the solvent evaporated. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain the title compound (59 mg, 45% yield) as a white solid. LRMS (m/z): 387 (M+1)+. 1H NMR (400 MHz, DMSO) δ 12.92 (s, 1 H), 8.10 (m, 2H), 7.94 (s, 1 H), 7.60 (s, 1 H), 7.53-7.34 (m, 4H), 6.93 (dd, 1 45 H), 6.64 - 6.54 (m, 1 H), 4.65 (s, 1 H), 1.98 (m, 2H), 0.77 (t, 3H).

EXAMPLE 16

(S)-2-(1-(6-aminopyrimidin-4-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one 50 [0242] 100 mg (0.37 mmol) of S ()-2-(1-aminopropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 130 mg (0.75 mmol) of 6-bromopyrimidine-4-amine and 130 PL (0.75 mmol) of diisopropylethylamine were suspended in 2 mL tert- butanol and the mixture was heated to 190 TC for 3 hours under microwave irradiation. Then the solvent was evaporated and the product was purified by preparative HPLC (Symmetry Prep C18 column, mixture of eluents A/B from 5% B to 55 45% B, in a 30 min. gradient). 10 mg (7% yield) were obtained as a white solid. LRMS (m/z): 362 (M+1)+. 1H NMR (400 MHz, DMSO) δ 8.52 (s, 1 H), 7.80 (s, 1 H), 7.67 - 7.38 (m, 5H), 7.04 (d, J = 6.9 Hz, 1 H), 6.93 (d, J = 2.7 Hz, 1 H), 6.64 - 6.49 (m, 1 H), 6.05 (s, 2H), 5.43 (s, 1 H), 4.28 (s, 1 H), 1.90 - 1.71 (m, 2H), 0.70 (t, J = 7.2 Hz, 3H).

58 EP 2 518 070 A1

EXAMPLE 17

(S)-2-(1-(2-amino-9H-purin-6-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

5 [0243] 60 mg (0.34 mmol) of ( S)-2-(1-aminopropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 76 mg (0.45 mmol) of 6-chloro-9H-purin-2-amine and 78 PL (0.45 mmol) of diisopropylethylamine were suspended in 2 mL tert-butanol and the mixture was heated to 150 TC for 1.5 hours under microwave irradiation. Then the solvent was evaporated and the product was purified by preparative HPLC (Symmetry Prep C18 column, mixture of eluents A/B from 10% B to 40% B, in a 25 min. gradient). 12 mg (13% yield) were obtained as a white solid. 10 LRMS (m/z): 402 (M+1)+. 1H NMR (400 MHz, DMSO) δ 12.11 (s, 1H), 8.27 (s, 1 H), 7.69 (s, 2H), 7.62 - 7.42 (m, 4H), 7.34 (s, 1 H), 6.92 (dd, J = 4.2, 1.6 Hz, 1 H), 6.56 (dd, J = 4.3, 2.7 Hz, 1 H), 5.59 (s, 2H), 4.55 (s, 1 H), 1.83 (m, 2H), 0.65 (t, J = 7.2 Hz, 3H).

EXAMPLE 18 15 (S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)propylamino)pyrimidine-5-carbonitrile

[0244] A suspension of 125 mg (0.33 mmol) of (S)-2-(1-aminopropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 20 56 mg (0.36 mmol) of 4-amino-6-chloropyrimidine-5-carbonitrile (prepared according to the procedure described in WO2010151735A2) and 170 PL (0.98 mmol) of diisopropylamine in 4 mL of tert-butanol was heated with stirring at 120 TC overnight. Then the solvent was removed under vacuum and the product was purified by flash chromatography (dichloromethane to dichloromethane/MeOH/NH40H, 100:8:1) followed by a second purification by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1 % v/v formic acid buffered] 0% 25 to 100%) to obtain the title compound (58 mg, 45% yield) as a white solid. LRMS (m/z): 387 (M+1)+. 1 H NMR (400 MHz, DMSO) δ 7.79 (s, 1 H), 7.67 (s, 1 H), 7.60 (d, J = 7.2 Hz, 1 H), 7.48 (d, J = 3.5 Hz, 2H), 7.40 - 7.29 (m, 3H), 7.23 (s, 2H), 6.95 (d, J = 2.8 Hz, 1 H), 6.64 - 6.57 (m, 1 H), 4.68 (dd, J = 13.3, 7.3 Hz, 1 H), 1.86 (ddt, J = 28.8, 13.9, 7.1 Hz, 2H), 0.75 (t, J = 7.2 Hz, 3H). 30 EXAMPLE 19

(R)-2-(1-(9H-purin-6-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

35 [0245] 70 mg (0.26 mmol) of racemic 2-(1-aminopropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 106 mg (0.53 mmol) of 6-bromo-9H-purine and 134 mg (1.04 mmol) of DIEA were suspended in 4 mL of tert-butanol and the mixture was heated to 80 TC for 40 hours. Then the solvent was removed in vacuo and the crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain 50 mg (50% yield) of racemic 2-(1-(9H-purin-6-ylamino)propyl)-3-phenylpyrrolo[1,2-f] 40 [1,2,4]triazin-4(3H)-one. [0246] The two enantiomers were separated by chiral HPLC with a Chiralpack IA column (5 Pm, 20x250 mm), eluting with a mixture of heptane/isopropanol/diethylamine (85/15/0.1) and 15 mg (15% yield) of the title enantiomer were obtained, corresponding to the second peak to elute (e.e. > 99.5%). LRMS (m/z): 387 (M+1)+. 45 1H NMR (400 MHz, DMSO) δ 12.88 (s, 1H),8.11 (m, 2H), 7.97 (s, 1 H), 7.62 - 7.56 (m, 1 H), 7.56 - 7.41 (m, 3H), 7.40 (s, 1 H), 7.29 (s, 1 H), 6.92 (dd, J = 4.2, 1.4 Hz, 1H), 6.56 (dd, J = 4.2, 2.7 Hz, 1H), 4.65 (s, 1H), 1.95 (m, 2H), 0.75 (t, J = 7.0 Hz, 3H).

EXAMPLE 20 50 (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0247] 90 mg (0.34 mmol) of ( S)-2-(1-aminopropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 134 mg (0.67 mmol) of 6-bromo-9H-purine and 174 PL (1.35 mmol) of diisopropylethylamine were suspended in 3 mL tert-butanol and the 55 mixture was heated to 100 TC for 40 hours. Then the solvent was removed in vacuo and the residue was taken up in AcOEt, washed with water and brine, dried over magnesium sulphate and the solvent evaporated. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain the title compound (59 mg, 45% yield) as a white solid.

59 EP 2 518 070 A1

LRMS (m/z): 373 (M+1)+. 1H NMR (400 MHz, DMSO) δ 12.92 (s, 1H), 8.19 - 7.95 (m, 3H), 7.68 - 7.42 (m, 4H), 7.29 (d, J = 17.2 Hz, 1H), 7.17 (s, 1H), 6.93 (dd, J = 4.3, 1.6 Hz, 1H), 6.58 (dd, J = 4.2, 2.7 Hz, 1H), 4.95 - 4.69 (m, 1H), 1.45 (d, J = 6.7 Hz, 3H).

5 EXAMPLE 21

(S)-2-(1-(2-amino-9H-purin-6-ylamino)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0248] 75 mg (0.29 mmol) of ( S)-2-(1-aminopropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 100 mg (0.59 mmol) 10 of 6-chloro-9H-purin-2-amine and 154 PL (0.88 mmol) of diisopropylethylamine were suspended in 2 mL of 2-propanol and the mixture was heated at 170 °C for 1 hour under microwave irradiation. Then the solvent was removed in vacuo and the residue was taken up in AcOEt, washed with water and brine, dried over magnesium sulphate and the solvent evaporated. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain the title compound (26 mg, 23% 15 yield) as a white solid. LRMS (m/z): 388 (M+1)+. 1H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 8.17 (s, 1H), 7.67 (s, 1H), 7.63 - 7.56 (m, 2H), 7.51 (s, 2H), 7.46 - 7.28 (m, 2H), 6.93 (dd, J = 4.3, 1.6 Hz, 1H), 6.57 (dd, J = 4.3, 2.7 Hz, 1H), 5.57 (s, 2H), 4.77 (s, 1H), 1.37 (d, J = 6.8 Hz, 3H).

20 EXAMPLE 22

(S)-2-(1-(6-aminopyrimidin-4-ylamino)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0249] 100 mg (0.39 mmol) of S ()-2-(1-aminopropyl)-3-phenyipyrroio[1,2-f][1,2,4]triazin-4(3H)-one, 136 mg (0.78 25 mmol) of 6-bromopyrimidin-4-amine and 274 PL (1.57 mmol) of diisopropylethylamine were suspended in 2 mL of N-methylpirrolidone and the mixture was heated at 170 TC for 1 hour under microwave irradiation, then at 180 TC for 2 hours and then at 200 TC for 4 hours. Then water was added to the reaction mixture and the product was extracted with dichloromethane. The organic layer was washed with water and brine, dried over MgSO4, filtered and the solvent was evaporated under vacuum. The product was purified by preparative HPLC (Symmetry Prep18 C column, mixture of 30 eluents A/B from 5% B to 45% B, in a 30 min. gradient). 23 mg (17% yield) were obtained as a solid. LRMS (m/z): 348 (M+1)+. 1H NMR (400 MHz, DMSO) δ 7.80 (s, 1H), 7.64 - 7.57 (m, 1H), 7.55 - 7.47 (m, 3H), 7.47 - 7.38 (m, 2H), 7.19 (s, 1H), 6.93 (dd, J = 4.2, 1.5 Hz, 1H), 6.58 (dd, J J = 4.3, 2.7 Hz, 1H), 6.12 (s, 2H), 5.39 (s, 1H), 4.48 (s, 1H), 1.30 (d, J = 6.8 Hz , 3H).

35 EXAMPLE 23

(S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile

40 [0250] 35 mg (0.14 mmol) of ( S)-2-(1-aminopropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 23 mg (0.15 mmol) of 4-amino-6-chloropyrimidine-5-carbonitrile (prepared according to the procedure described in WO2010151735A2) and 72 PL (0.41 mmol) of diisopropylethylamine were heated intert -butanol (2 mL) for 21 hours. Then the solvent was removed under vacuum and the crude product was purified by flash chromatography (0-10% methanol in dichloromethane) to give 26 mg (51% yield) of the title compound as a white solid. 45 LRMS (m/z): 348 (M+1)+. 1H NMR (400 MHz, DMSO) δ 7.76 (s, 1H), 7.73 - 7.64 (m, 2H), 7.52 - 7.46 (m, 1H), 7.43 (ddd, J = 8.0, 4.6, 2.3 Hz, 1H), 7.38 - 7.26 (m, 3H), 7.20 (s, 2H), 6.95 (dd, J = 4.3, 1.7 Hz, 1H), 6.61 (dd, J = 4.3, 2.7 Hz, 1H), 4.99 - 4.77 (m, 1H), 1.37 (d, J = 6.7 Hz, 3H).

50 EXAMPLE 24

2-(1-(6-amino-9H-purin-9-yl)ethyl)-5-methyl-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0251] 340 mg (0.90 mmol) of 2-(1-iodoethyl)-5-methyl-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one, 194 mg (1.44 55 mmol) of 9H-purin-6-amine and 310 mg (2.24 mmol) of potassium carbonate were heated in DMF (10 mL) at 50T C overnight. Then the solvent was removed under vacuum and water was added to the residue. A white solid precipitated and was stirred in water overnight. Then the solid was filtered and washed with water and the product was purified by flash chromatography (dichloromethane to dichloromethane/MeOH/NH40H, 100:8:1) to give 116 mg (34% yield) of the

60 EP 2 518 070 A1

title compound as a white solid. LRMS (m/z): 387 (M+1)+. 1H NMR (400 MHz, DMSO) δ 8.03 (s, 1H), 7.94 (s, 1H), 7.61 (dd, J = 6.7, 1.8 Hz, 1H), 7.55 (d, J = 2.7 Hz, 1H), 7.49 (td, J = 7.6, 1.3 Hz, 1H), 7.30 (tt, J = 7.5, 1.2 Hz, 1H), 7.19 (s, 2H), 7.09 (td, J = 7.7, 1.4 Hz, 1H), 6.76 (d, J = 8.0 Hz, 5 1H), 6.45 (dd, J = 2.7, 0.7 Hz, 1H), 5.44 (q, J = 6.8 Hz, 1H), 2.39 (s, 3H), 1.68 (d, J = 6.8 Hz, 3H).

EXAMPLE 25

2-((6-Amino-9H-purin-9-yl)methyl)-3-o-tolyl-5-(trifluoromethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one 10 [0252] This compound was prepared starting from 2-(chloromethyl)-3-o-tolyl- 5-(trifiuoromethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (2 mg, 0,006 mmol) and following the experimental procedure described in Example 1. Isolation of the compound was done by purification on a 5 g Bond Elut silica cartridge eluting with a mixture of dichloromethane/ methanol to afford 1 mg (50% yield) of the pure title compound. 15 LRMS (m/z): 441 (M+1)+.

EXAMPLE 26

2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one 20 [0253]

a) To a solution of di-tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodicarbonate (125 mg, 0,2 mmol) in 2,5 mL of dry 1,4-dioxane under argon atmosphere 132P L of aniline (1,45 25 mmol) were added and the mixture was heated to reflux with stirring overnight. At the end of this period, the reaction mixture was poured into 50 mL of a 4% aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2x40 mL). The organic layers were mixed and washed with more 4% aqueous solution of sodium bicarbonate, water and brine, and were dried (MgSO4) and concentrated under reduced presure to give 187 mg of a solid that was purified by flash chromatography silica (hexane/ethyl acetate). After purification were obtained 136 mg of di- 30 tert-butyl [9-(2-{[2-(anilinocarbonyl)-3-chloro-1H-pyrrol-1-yl]amino}-2-oxoethyl)-9H-purin-6-yl]imidodicarbonate (91 % yield).

b) To a solution of di-tert-butyl [9-(2-{[2-(anilinocarbonyl)-3-chloro-1H-pyrrol-1-yl]amino}-2-oxoethyl)-9H-purin-6-yl] imidodicarbonate (120 mg, 0,2 mmol) in 1,6 mL of dry 1,4-dioxane under argon atmosphere 179 PL of phosphorous 35 oxychloride (2 mmol) in 0,8 mL of dry 1,4-dioxane were added and the mixture was heated to reflux with stirring during 2 hours. Afterwards, the reaction mixture was concentrated to dryness coevaporating with toluene to remove traces of phosphorous oxychloride and the residue was suspenden in 1,2 mL of 7N ammonia in methanol heating the reaction at 60°C overnight. At the end of this period, the cooled reaction mixture was poured into 25 mL of a 1/1 mixture of water/ brine and extracted with ethyl acetate (2x20 mL). The organic layers were mixed and washed brine, 40 dried (MgSO4) and concentrated under reduced presure to give 45 mg of a solid that was purified by flash chromatography silica (dichloromethane/methanol). After purification were obtained 14 mg of the title compound of this example (18% yield).

LRMS (m/z): 393 (M+1)+. 45 1H NMR (600 MHz, dmso) δ 8.04 (s, 1H), 7.95 (s, 1H), 7.59 (d, J = 3.1 Hz, 1H), 7.53 - 7.46 (m, 5H), 7.23 (s, 2H), 6.66 (d, J = 3.1 Hz, 1H), 4.97 (s, 2H).

EXAMPLE 27

50 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(3-methoxyphenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0254]

a) To a solution of di-tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimi- 55 dodicarbonate (110 mg, 0,21 mmol) in 2 mL of dry 1,4- dioxane under argon atmosphere 160 PL of 3-methoxyaniline (1,25 mmol) were added and the mixture was heated to reflux with stirring overnight. At the end of this period, the reaction mixture was poured into 50 mL of a 4% aqueous solution of sodium bicarbonate and extracted with ethyl acetate(2x40 mL). Theorganic layers were mixedand washedwith more 4% aqueous solution of sodium bicarbonate,

61 EP 2 518 070 A1

water and brine, and were dried (MgSO 4) and concentrated under reduced presure to give a residue of 280 mg that was submitted to purification using a 10g Bond Elut silica cartridge eluting with a mixture of hexane/ethyl acetate. After purification were obtained 65 mg of di-tert butyl di-tert-butyl [9-(2-{[2-(3-methoxyphenylcarbamoyl)-3-chloro- 1H-pyrrol-1-yl]amino}-2-oxoethyl)-9H-purin-6-yl]imidodicarbonate (42% yield). 5 b) To a solution oftert -butyl di-tert-butyl [9-(2-{[2-(3-methoxyphenylcarbamoyl)-3-chloro-1H-pyrrol-1-yl]amino}-2- oxoethyl)-9H-purin-6-yl]imidodicarbonate (65 mg, 0,09 mmol) in 1 mL of dry 1,4-dioxane under argon atmosphere 100 PL of phosphorous oxychloride (1,1 mmol) in 0,5 mL of dry 1,4- dioxane were added and the mixture was heated to reflux with stirring during 2 hours. Afterwards, the reaction mixture was concentrated to dryness co-evaporating 10 with toluene to remove traces of phosphorous oxychloride and the residue was suspenden in 1 mL of 7N ammonia in methanol heating the reaction at 60 TC overnight. At the end of this period, the cooled reaction mixture was poured into 25 mL of a 4% aqueous solution of sodium bicarbonate and extracted with ethyl acetate (3x25 mL). The organic layers were mixed and washed brine, dried (MgSO4) and concentrated under reduced presure to give a residue that was purified by flash chromatography silica (dichloromethane/methanol). After purification were obtained 12 15 mg of the title compound of this example (30% yield).

LRMS (m/z): 423 (M+1)+. 1H NMR (400 MHz, dmso) δ 12.02 (s, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.60 (d, J = 3.0 Hz, 1H), 7.39 (dd, J = 9.1, 7.7 Hz, 1H), 7.22 (s,2H), 7.06- 6.96 (m,3H), 6.66(d, J = 3.0 Hz, 1H), 5.07 (d, J = 16.8 Hz, 1H), 4.99 (d, J = 16.8 Hz,1H), 3.73 (s , 3H). 20 EXAMPLE 28

2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(2,4-difluorophenyl)pyrrolo-[1,2-f][1,2,4]triazin-4(3H)-one

25 [0255]

a) Sodium hexamethyldisilazide (1M solution in tetrahydrofurane, 965 PL, 0,97 mmol) was added to a solution of 2,4-difluoroaniline (118 PL, 1,16 mmol) in 0,5 mL of dry tetrahydrofurane under argon and the mixture was stirred at room temperature during 15 minutes. At the end of this period, the mixture was put in an ice-water bath and a 30 solution of di-tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodicarbonate (100 mg, 0,19 mmol) in 2 mL of tetrahydrofurane was added mateining the stirring during 30 minutes at room temperature. Next, the reaction mixture was poured into 25 mL of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (2x20 mL). The organic layers were mixed and washed water and brine, dried (MgSO4) and concentrated under reduced presure to give 145 mg of an oil that was purified by flash chroma- 35 tography silica (dichloromethane/ methanol). After purification were obtained 68 mg of tert-butyl 9-(2-(3-chloro-2-(2,4- difluorophenylcarbamoyl)-1H-pyrrol-1-ylamino)-2-oxoethyl)-9H-purin-6-ylcarbamate (65% yield).

b) To a solution oftert -butyl 9-(2-(3-chloro-2-(2,4-difluorophenylcarbamoyl)-1H-pyrrol-1-ylamino)-2-oxoethyl)- 9H-purin-6-ylcarbamate (60 mg, 0,09 mmol) in 0,8 mL of dry 1,4-dioxane under argon atmosphere 85 PL of phos- 40 phorous oxychloride (0,93 mmol) in 0,4 mL of dry 1,4-dioxane were added and the mixture was heated to reflux with stirring during 2 hours. Afterwards, the reaction mixture was concentrated to dryness coevaporating with toluene to remove traces of phosphorous oxychloride and the residue was suspenden in 2,4 mL of 7N ammonia in methanol heating the reaction at 60°C overnight. At the end of this period, the cooled reaction mixture was poured into 25 mL of a 1/1 mixture of water/ brine and extracted with chloroform (3x25 mL). The organic layers were mixed and washed 45 brine, dried (MgSO4) and concentrated under reduced presure to give 41 mg of a solid that was purified by flash chromatography silica (dichloromethane/methanol). After purification were obtained 9 mg of the title compound of this example (23% yield).

LRMS (m/z): 429 (M+1)+. 50 1H NMR (600 MHz, dmso) δ 7.95 (s, 1H), 7.89 (s, 1H), 7.70 (m, 1H), 7.64 (d, J = 3.0 Hz, 1H), 7.34 (m, 1H), 7.22 (m, 1H), 7.20 (s, 2H), 6.67 (d, J = 3.0 Hz, 1H), 5.04 (dd, J = 16.7 Hz, 2H).

EXAMPLE 29

55 2-((6-Amino-9H-purin-9-yl)methyl)-3-benzyl-5-chloropyrrolo[1,2-f][1,2,4]-triazin-4(3H)-one

[0256]

62 EP 2 518 070 A1

a) To a solution di- tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodicarbonate (100 mg, 0,2 mmol) in 2 mL of dry 1,4-dioxane under argon atmosphere 127 PL of benzylamine (1,16 mmol) were added and the mixture was stirred at 30 TC during 2 hours. At the end of this period, the reaction mixture was concentrated to dryness under reduced presure and the residue was purified by flash chromatography silica 5 (dichloromethane/methanol). After purification were obtained 95 mg of tert-butyl 9-(2-(2-(benzylcarbamoyl)-3-chloro- 1H-pyrrol-1-ylamino)-2-oxoethyl)-9H-purin-6-ylcarbamate (92% yield).

b) To a solution of tert-butyl 9-(2-(2-(benzylcarbamoyl)-3-chloro-1H-pyrrol-1-ylamino)-2-oxoethyl)-9H-purin-6-ylcarbamate (95 mg, 0,18 mmol) in 1,32 mL of dry 1,4-dioxane under argon atmosphere 165P L of phosphorous oxy- 10 chloride (1,8 mmol) in 0,6 mL of dry 1,4- dioxane were added and the mixture was heated to reflux with stirring during 2 h. Afterwards, the reaction mixture was concentrated to dryness coevaporating with toluene to remove traces of phosphorous oxychloride and the residue was suspenden in 3,8 mL of 7N ammonia in methanol heating the reaction at 60TC overnight. At the end of this period, the cooled reaction mixture was poured into 25 mL of a 1/1 mixture of water/brine and extracted with chloroform (3x25 mL). The organic layers were mixed and washed brine, dried 15 (MgSO4) and concentrated under reduced presure to give 57 mg of a solid that was purified by reverse phase chromatography (C-18 silica from Waters, water/ 1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%). After purification were obtained 11 mg of the title compound of this example (15% yield).

LRMS (m/z): 407 (M+1)+. 20 1H NMR (600 MHz, dmso) δ 8.13 (s, 1H), 8.08 (s, 1H), 7.51 (d, J = 3.0 Hz, 1H), 7.49 - 7.28 (m, 5H), 7.25 (s, 2H), 6.64 (d, J = 3.0 Hz, 1H), 5.46 (s, 2H), 5.33 (s, 2H).

EXAMPLE 30

25 2-((6-amino-9H-purin-9-yl)methyl)-3-phenylimidazo[1,2-f][1,2,4]triazin-4(3H)-one

[0257] 9H-purin-6-amine (85 mg, 0.63 mmol) and potassium carbonate (87 mg, 0.63 mmol) were added to a solution of 2-(chioromethyl)-3-phenylimidazo[1,2-f][1,2,4]triazin-4(3H)-one (137 mg, 0.53 mmol) in 10 mL of DMF. The mixture was stirred at room temperature for 21 hours. The solvent was evaporated to dryness and the crude product was purified 30 by flash chromatography (10% to 20% MeOH/DCM) to yield 100 mg (53% yield) of the title compound as a white solid. LRMS (m/z): 360 (M+1)+. 1H NMR (250 MHz, DMSO) δ 8.05 (s, 1H), 7.98 (m, 2H), 7.53 (m, 6H), 7.25 (bs, 2H), 5.04 (s, 2H).

EXAMPLE 31 35 2-((6-amino-9H-purin-9-yl)methyl)-3-o-tolylimidazo[1,2-f][1,2,4]triazin-4(3H)-one

[0258] 9H-purin-6-amine (207 mg, 1.53 mmol) and potassium carbonate (211 mg, 1.53 mmol) were added to a solution of 2-(chloromethyl)-3-o-tolylimidazo[1,2-f][1,2,4]triazin-4(3H)-one (350 mg, 1.27 mmol) in 20 mL of DMF. The mixture 40 was stirred at room temperature for 5 hours and poured into water. A 10% aqueous solution of sodium hydroxide was added until the solution reached pH=11 and then the product was extracted with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and the solvent was evaporated. The crude product was triturated with dichloromethane (5 mL) and methanol (5 mL) and 130 mg (27% yield) of the title compound ere obtained as a white solid. LRMS (m/z): 374 (M+1)+. 45 1H NMR (250 MHz, DMSO) δ 8.02 (m, 3H), 7.51 (m, 5H), 7.24 (bs, 2H), 5.12 (s, J = 16.0 Hz, 1H), 4.86 (s, J = 16.0 Hz, 1H), 2.13 (s, 3H)

EXAMPLE 32

50 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(pyridin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0259]

a) To a suspensión of 4-aminopyridine (164 mg, 1,74 mmol) in 3,3 mL of dichloromethane under inert atmosphere 55 was added a 2M solution of trimethyl aluminium in toluene (0,87 mL, 1,74 mmol) and the mixture was stirred during 20 minutes at room temperature. Next, this mixture was cooled in an ice-water bath and a solution of di-tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodicarbonate (150 mg, 0,29 mmol) in 2,2 mL of dry dichloromethane was added stirring the mixture during 3 days at room temperature. At the

63 EP 2 518 070 A1

end of this period, the reaction mixture was cooled-down with an ice-water bath and 5 mL of water were added followed by a 5% aqueous solution disodium tartrate dihidrate. The resulting mixture was purified directly by reverse phase chromatography (C-18 silica from Waters, water/1:1 acetonitrile-methanol as eluents 0% to 100%). After purification were obtained 139 mg of tert-butyl 9-(2-(3-chloro-2-(pyridin-4-ylcarbamoyl)-1H-pyrrol-1-ylamino)-2-ox- 5 oethyl)-9H-purin-6-ylcarbamate (93% yield).

b) Starting from tert-butyl 9-(2-(3-chloro-2-(pyridin-4-ylcarbamoyl)-1H-pyrrol-1-ylamino)-2-oxoethyl)-9H-purin-6-ylcarbamate (131 mg, 0,26 mmol) and following the experimental procedure described in Example 26b were obtained 4,2 mg (3,5% yield) of the title compound of this example. 10 LRMS (m/z): 394 (M+1)+. 1H NMR (600 MHz, dmso) δ 8.61 (dd, J = 4.5, 1.6 Hz, 2H), 7.95 (s, 1H), 7.90 (s, 1H), 7.59 (d, J = 3.0 Hz, 1H), 7.44 (dd, J = 4.5, 1.6 Hz, 2H), 7.18 (s, 2H), 6.64 (d, J = 3.1 Hz, 1H), 4.97 (s, 2H).

15 EXAMPLE 33

2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(tetrahydro-2H-pyran-4-yl)pyrrolo-[1,2-f][1,2,4]triazin-4(3H)-one

[0260] 20 a) Starting from di- tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodicarbonate (131 mg, 0,26 mmol) and following the experimental procedure described in Example 26a but heating the reaction mixture at 80°C during 4 hours were obtained 170 mg (70% yield) of di-tert-butyl {9-[2-oxo-2-({2-[(tetrahydro-2H-pyran-4-ylamino)carbonyl]-1H-pyrrol-1-yl}amino)ethyl]-9H-purin-6-yl}imidodicarbonate. 25 b) Starting from di-tert butyl {9-[2-oxo-2-({2-[(tetrahydro-2H-pyran-4-yiamino)carbonyl]-1H-pyrrol-1-yl}amino)ethyl]- 9H-purin-6-yl}imidodicarbonate (131 mg, 0,26 mmol) and using the conditions described in Example 26b but isolating the product in the following way: the crude was concentrated to dryness and the residue obtained was precipitated from a 1/1 mixture of dimethylsulfoxide/4% aqueous solution of sodium bicarbonate to afford 43 mg after filtration 30 (36% yield) of the title compound of this example.

LRMS (m/z): 401 (M+1)+. 1H NMR (600 MHz, dmso) δ 8.22 (s, 1H), 8.21 (s, 1H), 7.51 (d, J = 3.0 Hz, 1H), 7.38 (s, 2H), 6.62 (d, J = 3.0 Hz, 1H), 5.62 (s, 2H), 4.18 - 4.09 (m, 1H), 3.84 - 3.76 (m, 2H), 3.08 - 2.99 (m, 2H), 2.67 - 2.57 (m, 2H), 1.35 - 1.26 (m, 2H). 35 EXAMPLE 34

2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(1-methylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

40 [0261]

a) Starting from di- tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodicarbonate (150 mg, 0,29 mmol) and following the experimental procedure described in Example 26a but heating the reaction mixture at 100TC during 4 hours were obtained 136 mg (86% yield) oftert -butyl 9-(2-(3-chloro-2-(1- 45 methylpiperidin-4-ylcarbamoyl)-1H-pyrrol-1-ylamino)-2-oxoethyl)-9H-purin-6-ylcarbamate.

b) Starting fromtert -butyl 9-(2-(3-chloro-2-(1-methylpiperidin-4-ylcarbamoyl)-1H-pyrrol-1-ylamino)-2-oxoethyl)- 9H-purin-6-ylcarbamate (128 mg, 0,24 mmol) and following the experimental procedure described in Example 33b were obtained 21 mg (21 % yield) of the title compound of this example. 50 LRMS (m/z): 414 (M+1)+. 1H NMR (600 MHz, dmso) δ 8.21 (s, 1H), 8.21 (s, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.36 (s, 2H), 6.62 (d, J = 2.5 Hz, 1H), 5.55 (s, 2H), 3.90 - 3.67 (m, 1H), 2.74 - 2.54 (m, 4H), 2.05 (s, 3H), 1.63 - 1.44 (m, 2H), 1.31 - 1.13 (m, 2H).

55

64 EP 2 518 070 A1

EXAMPLE 35

(S)-2-(1-(9H-Purin-6-ylamino)ethyl)-3-(3-fluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

5 [0262] Starting from (S)-2-(1-aminoethyl)-3-(3-fluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (23 mg, 0,08 mmol) and following theexperimental procedure described in Example 26bwere obtained 18 mg(50% yield) of thetitle compound of this example. LRMS (m/z): 391 (M+1)+. 1H NMR (400 MHz, dmso) δ 12.92 (s, 1H), 8.11-8.00 (2s, 1H), 7.68 (m, 1H), 7.58 - 7.07 (m, 2H), 6.95 (m, 1H), 6.60 (m, 10 1H), 4.95 (m, 1H), 4.84 (m, 1H), 1.47 (d, J = 6.6 Hz, 3H).

EXAMPLE 36

(S)-4-Amino-6-(1-(3-(3-fluorophenyl)-4-oxo-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine- 15 5-carbonitrile

[0263] Starting from (S)-2-(1-aminoethyl)-3-(3-fluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (23 mg, 0,08 mmol) and following theexperimental procedure described in Example 26bwere obtained 13 mg(36% yield) of thetitle compound of this example. 20 LRMS (m/z): 391 (M+1)+. 1H NMR (400 MHz, dmso) δ 7.78, 7.74 (2s, 1H), 7.73-7.67 (m, 1H), 7.55-7.27 (m, 2H), 7.22 (brs, 2H), 7.17-7.11 (m, 2H), 6.97 (m, 1H), 6.63 (m, 1H), 5.07 - 4.92 (m, 1H), 4.84 (m, 1H), 1.38 (d, J = 6.5 Hz, 3H).

EXAMPLE 37 25 (S)-2-(1-(9H-Purin-6-ylamino)ethyl)-3-(3,5-difluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0264] Starting from S ( )-2-(1-aminoethyl)-3-(3,5-difluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (17 mg, 0,06 mmol) and following the experimental procedure described in Example 26b were obtained 18 mg (71 % yield) of the title 30 compound of this example. LRMS (m/z): 409 (M+1)+. 1H NMR (600 MHz, dmso) δ 12.92 (s, 1H), 8.15 - 7.95 (m, 3H), 7.71 (s, 1H), 7.48 (m, 1H), 7.10 - 7.01 (m, 1H), 6.99 - 6.94 (m, 1H), 6.66 - 6.58 (m, 1H), 5.15 - 5.04 (m, 1H), 4.64 (m, 1H), 1.48 (d, J = 6.7 Hz, 2H).

35 EXAMPLE 38

(S)-4-Amino-6-(1-(3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile

40 [0265] Starting from S ( )-2-(1-aminoethyl)-3-(3,5-difluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (17 mg, 0,06 mmol) and following the experimental procedure described in Example 26b were obtained 13 mg (41 % yield) of the title compound of this example. LRMS (m/z): 409 (M+1)+. 1H NMR (600 MHz, dmso) δ 7.78 (s, 1H), 7.75 (dd, J = 2.7, 1.7 Hz, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.47 (m, 1H), 7.25 (bs, 45 2H), 7.18 (m, 1H), 6.99 (dd, J = 4.2, 1.7 Hz, 1H), 6.64 (dd, J = 4.3, 2.7 Hz, 1H), 5.15 - 5.04 (m, 1H), 4.68 - 4.61 (m, 1H), 1.39 (d, J = 6.6 Hz, 2H).

EXAMPLE 39

50 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-methylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0266]

a) Starting from di- tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodi- 55 carbonate (150 mg, 0,29 mmol) and following the experimental procedure described in Example 26a but using tetrahydrofurane as solvent and stirring the reaction mixture at room temperature during 2 hours were obtained 126 mg (97% yield) of tert-butyl 9-(2-(3-chloro-2-(methylcarbamoyl)-1H-pyrrol-1-ylamino)-2-oxoethyl)-9H-purin-6-ylcarbamate.

65 EP 2 518 070 A1

b) Starting from tert-butyl 9-(2-(3-chloro-2-(methylcarbamoyl)-1H-pyrrol-1-ylamino)-2-oxoethyl)-9H-purin-6-ylcarbamate (125 mg, 0,28 mmol) and following the experimental procedure described in Example 33b were obtained 46 mg (48% yield) of the title compound of this example.

5 LRMS (m/z): 331 (M+1)+. 1H NMR (400 MHz, dmso) δ 8.15 (s, 1H), 8.15 (s, 1H), 7.42 (d, J = 3 Hz, 1H), 7.32 (s, 2H), 6.57 (d, J = 3 Hz, 1H), 5.58 (s, 2H), 3.46 (s, 3H).

EXAMPLE 40 10 2-((6-Amino-9H-purin-9-yl)methyl)-3-((1r,4r)-4-aminocyclohexyl)-5-chloropyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0267]

15 a) Starting from di- tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodicarbonate (150 mg, 0,29 mmol) and following the experimental procedure described in Example 26a but heating the reaction mixture at 50°C during 2 hours were obtained 138 mg (82% yield) tertof -butyl 9-(2-(2-((1 r,4r)-4- aminocyclohexylcarbamoyl)-3-chloro-1H-pyrrol-1-ylamino)-2-oxoethyl)-9H-purin-6-ylcarbamate.

20 b) Starting from tert-butyl 9-(2-(2-((1r,4r)-4-aminocyclohexylcarbamoyl)-3-chloro-1H-pyrrol-1-ylamino)-2-oxoethyl)- 9H-purin-6-ylcarbamate (130 mg, 0,24 mmol) and using the conditions described in Example 26b but isolating the product in the following way: the crude was concentrated to dryness and the residue obtained was purified by reverse phase chromatography (C-18 silica from Waters, water/1:1 acetonitrile-methanol as eluents 0% to 100%). After purification were obtained 14 mg (13% yield) of the title compound of this example. 25 LRMS (m/z): 414 (M+1)+. 1H NMR (600 MHz, dmso) δ 8.20 (s, 1H), 8.20 (s, 1H), 7.50 (d, J = 3.0 Hz, 1H), 7.35 (s, 2H), 6.61 (d, J = 3.0 Hz, 1H), 5.55 (s, 2H), 3.88 - 3.79 (m, 1H), 2.40 - 2.37 (m, 1H), 1.67 - 1.58 (m, 4H), 1.35 - 1.27 (m, 2H), 0.83 - 0.74 (m, 4H).

30 EXAMPLE 41

(R)-2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(1-phenylethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0268] 35 a) Starting from di- tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodicarbonate (150 mg, 0,29 mmol) and following the experimental procedure described in Example 26a but heating the reaction mixture at 40°C during 1.5 hours were obtained 138 mg (78% yield) oftert -butyl [9-(2-{[3-chloro-2-({[ (1R)-1-phenylethyl]amino}carbonyl)-1H-pyrrol-1-yl]amino}-2-oxoethyl)-9H-purin-6-yl]carbamate. 40 b) A solution of bromine (37 mg, 0,24 mmol) in dichloromethane (100P L) was added dropwise to a solution of triphenylphosphine (63 mg, 0.24 mmol) in dichloromethane (1 ml) under nitrogen. The solution was stirred for 30 min, and triethylamine (78 PL, 0.56 mmol) and tert-butyl [9-(2-{[3-chloro-2-({[(1R)-1-phenylethyl]amino}carbonyl)- 1H-pyrrol-1-yl]amino}-2-oxoethyl)-9H-purin-6-yl]carbamate (100 mg, 0.19 mmol) were added. The reaction mixture 45 was refluxed for 1.5 h, and quenched with 10 % aqueous sodium bicarbonate solution. The organic phase was separated, dried (sodium sulphate) and concentrated to obtain an oil that was treated with 6 ml of a 7M methanolic solution of ammonia at 60 TC in a sealed vessel. The solvent was then evaporated to obtain 66 mg (34% yield, 48% purity) of tert-butyl [9-({5-chloro-4-oxo-3-[(1R)-1-phenylethyl]-3,4-dihydropyrroio[2,1-f][1,2,4]triazin-2-yl}methyl)- 9H-purin-6-yl]carbamate. 50 c) tert-Butyl [9-({5-chioro-4-oxo-3-[(1R)-1-phenylethyl]-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl}methyl)-9H-purin- 6-yl]carbamate (66 mg, 48% purity, 0,061 mmol) were disolved in 4 ml of a 4M hydrogen chloride solution in dioxane and heated to 45°C for 1 hour. Then, the crude was concentrated to dryness and the residue obtained was purified by flash chromatography silica (dichloromethane/ methanol). After purification were obtained 22 mg of the title com- 55 pound of this example (85% yield).

LRMS (m/z): 421 (M+1)+. 1H NMR (400 MHz, dmso) δ 8.21 (s, 1H), 8.11 (s, 1H), 7.47 (d, J = 3.0 Hz, 1H), 7.40 - 7.21 (m, 7H), 6.58 (d, J = 3.0 Hz,

66 EP 2 518 070 A1

1H), 5.80 (m, 1H), 5.58 (m, 2H), 1.81 (d, J = 6.6 Hz, 3H).

EXAMPLE 42

5 (S)-2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(1-phenylethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0269]

a) Starting from di- tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodi- 10 carbonate (150 mg, 0,29 mmol) and following the experimental procedure described in Example 26a but heating the reaction mixture at 40°C during 1.5 hours were obtained 132 mg (75% yield) oftert -butyl [9-(2-{[3-chloro-2-({[ (1S)-1-phenylethyl]amino}carbonyl)-1H-pyrrol-1-yl]amino}-2-oxoethyl)-9H-purin-6-yl]carbamate.

b) Starting from tert-butyl [9-(2-{[3-chloro-2-({[(1S)-1-phenylethyl]amino}carbonyl)-1H-pyrrol-1-yl]amino}-2-oxoe- 15 thyl)-9H-purin-6-yl]carbamate (132 mg, 0,24 mmol) and following the experimental procedure described in Example 41 b were obtained 132 mg (55% yield, 52% purity) tert of -butyl [9-({5-chloro-4-oxo-3-[(1S)-1-phenylethyl]-3,4- dihydropyrroio[2,1-f][1,2,4]triazin-2-yl}methyl)-9H-purin-6-yl]carbamate.

c) Starting from tert-butyl tert-butyl[9-({5-chloro-4-oxo-3-[(1S)-1-phenylethyl]-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin- 20 2-yl}methyl)-9H-purin-6-yl]carbamate (132 mg, 52 % purity, 0.13 mmol) and following the experimental procedure described in Example 41 c were obtained 48 mg of the title compound of this example (87% yield).

LRMS (m/z): 421 (M+1)+. 1H NMR (400 MHz, dmso) δ 8.21 (s, 1H), 8.11 (s, 1H), 7.47 (d, J = 3.0 Hz, 1H), 7.39 - 7.20 (m, 7H), 6.59 (d, J = 3.0 Hz, 25 1H), 5.80 (s, 1H), 5.53 (m, 2H), 1.81 (d, J = 6.7 Hz, 3H).

EXAMPLE 43

(S)-4-amino-6-(1-(4-oxo-3-(pyridin-2-yl)-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine- 30 5-carbonitrile

[0270] Starting from ( S)-2-(1-aminoethyl)-3-(pyridin-2-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one dihydrochloride (60 mg, 0,13 mmol) and following the experimental procedure described in Example 23 were obtained 8 mg (9% yield) of the title compound of this example. 35 LRMS (m/z): 374 (M+1)+. 1H NMR (400 MHz, dmso) δ 8.47 (d, J = 4.0 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.75 (m, 2H), 7.69 (d, J = 7.4 Hz, 1H), 7.44 (bd, J = 6.6 Hz, 1H), 7.37 - 7.29 (m, 1H), 7.21 (bs, 2H), 7.01 (dd, J = 4.3, 1.6 Hz, 1H), 6.65 (dd, J = 4.3, 2.7 Hz, 1H), 5.10 (m, 1H), 1.40 (d, J = 6.7 Hz, 4H).

40 EXAMPLE 44

(S)-2-(1-(9H-purin-6-yl)pyrrolidin-2-yl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

[0271] 45 mg (0.16 mmol) of ( S)-3-phenyl-2-(pyrrolidin-2-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3Hone, 35 mg (0.17 mmol) of 45 6-bromo-9H-purine and 25 Pl (0.17 mmol) of diisopropylethylamine were stirred in tert-butanol (5 ml) at 80 TC overnight. Then the solvent was removed in vacuo and the residue was taken up in AcOEt, washed with water and brine, dried over magnesium sulphate and the solvent evaporated. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1 % v/v formic acid buffered] 0% to 100%) to obtain the title compound (22 mg, 80% yield) as a white solid. 50 LRMS (m/z): 399 (M+1)+.

55

67 EP 2 518 070 A1

EXAMPLE 45

(S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(pyridin-2-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

5 EXAMPLE 46

(S)-4-amino-6-(1-(4-oxo-3-phenyl-5-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino) pyrimidine-5-carbonitrile

10 EXAMPLE 47

(S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenyl-5-(trifluoromethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

EXAMPLE 48 15 (S)-4-amino-6-(1-(5-(difluoromethyl)-4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile

EXAMPLE 49 20 (S)-2-(1-(9H-purin-6-ylamino)ethyl)-5-(difluoromethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

EXAMPLE 50

25 (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenylimidazo[1,2-f][1,2,4]triazin-4(3H)-one

EXAMPLE 51

(S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydroimidazo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbon- 30 itrile

EXAMPLE 52

(S)-2-(1-(9H-purin-6-ylamino)propyl)-3-phenylimidazo[1,2-f][1,2,4]triazin-4(3H)-one 35 EXAMPLE 53

(S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydroimidazo[1,2-f][1,2,4]triazin-2-yl)propylamino)pyrimidine-5-carbonitrile 40 EXAMPLE 54

2-(1-(9H-purin-6-ylamino)-3,3,3-trifluoropropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

45 EXAMPLE 55

4-amino-6-(3,3,3-trifluoro-1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)propylamino)pyrimidine-5-carbonitrile

50 EXAMPLE 56

(S)-4-amino-6-(2-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile

55 REFERENCES

[0272]

68 EP 2 518 070 A1

1.- Tehrani, A. K.; Borremans D.; De Kimpe N. Tetrahedron 1999, 55, 4133-4152 2.- Ohta, T.; Fukuda, T.; Ishibashi, F., Iwao, M. J. Org. Chem. 2009, 74, 8143-8153

PHARMACOLOGICAL ACTIVITY 5 PI3K α, β, δ and γ Enzymatic Inhibition Assays

[0273] Compounds were screened for their ability to inhibit PI3Kα (PI3Kα), PI3Kβ (PI3Kb), PI3Kδ (PI3Kd) and PI3Kγ (PI3Kg) using a cell-free based P13K HTRF™ assay (Millipore, ref. #33-017) All reagents to perform the reactions were 10 prepared according to the manufacturer protocol. All PI3K enzymes were recombinant and were purchased at Millipore. [0274] All four assays were performed according to the following procedure:

1) Dilution curves of compounds were done in 100% DMSO and dispensed in a reservoir plate, typically from column 2 to 11. Column 1 and 12 were used for the negative controls (100% inhibition using a reference PI3K inhibitor for 15 the four isoforms) and the positive controls (0% inhibition using dimethyl sulfoxide (DMSO) only). 2) Mix of Phosphoinositide 3-kinase (Pl3K) + Phosphatidylinositol 4,5-bisphosphate (PIP2) was diluted in buffer (supplied with the kit) and plated in a medium binding black 96- well plate (Greiner ref. #675076) PI3Ka was diluted at 0.25 nM with PIP2 at 2 PM; PI3Kb was diluted at 0.50 nM with PIP2 at 5 PM; PI3Kd was diluted at 0.60 nM with PIP2 at 2 PM and PI3Kg was diluted at 0.30 nM with PIP2 at 10 PM. These concentrations were final in the assay. 20 3) A reservoir plate containing Adenosine TriPhosphate (ATP) diluted in the Millipore kit buffer was prepared for each isoform. The final concentration of ATP in the assay was 10PM, 15 PM, 20 PM and 10 PM for PI3Ka, PI3Kb, .PI3Kd and PI3Kg respectively. 4) Reactions were started by addition to the PI3K+PIP2 plates of the ATP and compounds simultaneously. Incubation was done for 8 minutes (for all four isoforms) then the reaction was stopped by addition of the Stop solution. The 25 Detection solution was added. These solutions were prepared previously according to the kit specifications. The plates were then incubated overnight at RT before reading the signal in an Envision (PerkinElmer), with excitation at 340 nm and emissions at 620 and 665 nm. 5) Data obtained from the compound curves were normalized in respect to the negative and positive controls, and then fitted by a 4-parameter log curve in ActivityBase (IDBS) in order to determine their potency. 30 [0275] The results are shown in Table 1.

Example IC50 PI3Kd HTRF (nM)

35 1 119.02 11 118.75 15 17.73 17 9.37 40 21 4.52 25 347.39 29 375.56

45 31 6566.23 37 15.25 43 12.65 44 29.02 50

[0276] It can be seen from Table 1 that the compounds of formula (I) are potent inhibitors of Phosphoinositide 3-kinase delta (PI3kd). Preferred compounds of the invention possess an IC50 value for the inhibition of PI3Kd (determined as defined above) of less than 10 PM (10,000 nM), preferably less than 1 PM (1,000 nM), even more preferably of less

55 than 0.2 PM (200 nM), most preferably less than 0.05 PM (50 nM) [0277] The invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders,

69 EP 2 518 070 A1

or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

Combinations 5 [0278] The pyrrolotriazinone derivatives defined herein may also be combined with other active compounds in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of PI3Ks. [0279] The combinations of the invention can optionally comprise one or more additional active substances which are known to be useful in the treatment of respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated 10 diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo- dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors. [0280] Particularly, the combinations of the invention can optionally comprise one or more additional active substances 15 which are known to be useful in the treatment of neoplastic diseases (e.g. leukemia, lymphomas, solid tumors); transplant rejection, bone marrow transplant applications (e.g., graft- versus- host disease); autoimmune diseases (e.g. rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes); respiratory inflammation diseases (e.g. asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis); allergic diseases (e.g. allergic rhinitis); 20 skin inflammatory diseases (e.g., atopic dermatitis, contact dermatitis, eczema or psoriasis); premalignant and malignant skin conditions (e.g. basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or actinic keratosis (AK)); neurological disorders and pain (such as pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, inflammatory neuropathic pain, trigeminal neuralgia or central pain) [0281] Preferably, the combinations of the invention can optionally comprise one or more additional active substances 25 which are known to be useful in the treatment of neoplastic diseases leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis. 30 [0282] The combinations of the invention comprise (i) a compound of the invention as defined above; and (ii) another compound selected from the group consisting of an Adenoside A 2A agonist, an agent for treating cardiovascular disorders, an agent for treating diabetes, and an agent for treating liver disease, an anti-allergic agent, an anti-cholinergic agent, an anti-inflammatory agent, an anti-infective agent, a β2-adrenergic agonist, a Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitor, a chemotherapeutic agent, a corticosteroid, an IKKβ/IKBKB (IkB 35 kinase beta or IKK2) inhibitor, an immunosuppressant, a Janus kinase (JAK) inhibitor, a topically acting p38 Mitogen- Activated Protein Kinase (p38 MAPK) inhibitor, a Phosphosdiesterase (PDE) IV inhibitor, and a Spleen tyrosine kinase (Syk) inhibitor, for simultaneous, separate or sequential use in the treatment of the human or animal body. [0283] In a particular embodiment, the combinations of the invention can optionally comprise one or more additional active substances selected from 40 a) Dyhydrofolate reductase inhibitors, such as Methotrexate or CH-1504; b) Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide, or the compounds described in the International Patent Application Nos. WO2008/077639 and WO2009/021696; c) Immunomodulators such as Glatiramer acetate (Copaxone), Laquinimod or Imiquimod; 45 d) Inhibitors of DNA synthesis and repair, such as Mitoxantrone or Cladribine; e) Immunosuppressants, such as Imuran (azathioprine) or Purinethol (6-mercaptopurine or 6-MP); f) Anti-alpha 4 integrin antibodies, such as Natalizumab (Tysabri) ; g) Alpha 4 integrin antagonists such as R-1295 , TBC-4746, CDP-323, ELND-002, Firategrast or TMC-2003; h) Corticoids and glucocorticoids such as prednisone or methylprednisolone, fluticasone, mometasone, budesonide, 50 ciclesonide or beta-metasone; i) Fumaric acid esters, such as BG-12; j) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal antibodies such as Infliximab, Adalimumab or Cer- tolizumab pegol; k) Soluble Tumor necrosis factor-alpha (TNF-alpha) Antagonists such as Ethanercept; 55 l) Anti-CD20 (lymphocyte protein) monoclonal antibodies such as Rituximab, Ocrelizumab Ofatumumab or TRU-015; m) Anti-CD52 (lymphocyte protein) monoclonal antibodies such as alemtuzumab; n) Anti-CD25 (lymphocyte protein) such as daclizumab; o) Anti-CD88 (lymphocyte protein), such as eculizumab or pexilizumab;

70 EP 2 518 070 A1

p) Anti-Interleukin 6 Receptor (IL-6R), such as tocilizumab; q) Anti-Interleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-23R), such as ustekinumab; r) Calcineurin inhibitors such as cyclosporine A or tacrolimus; s) Inosine-monophosphate dehydrogenase (IMPDH) inhibitors, such as mycophenolate mophetyl, ribavirin, mizori- 5 bine or mycophenolic acid; t) Cannabinoid receptor agonists such as Sativex; u) Chemokine CCR1 antagonists such as MLN-3897 or PS-031291; v) Chemokine CCR2 antagonists such as INCB-8696; w) Necrosis factor-kappaB (NF-kappaB or NFKB) Activation Inhibitors such as Sulfasalazine, Iguratimod or MLN- 10 0415; x) Adenosine A2A agonists, such as ATL-313, ATL-146e, CGS-21680, Regadenoson or UK-432,097; y) Sphingosine-1 (S1 P) phosphate receptor agonists such as fingolimod, BAF-312, or ACT128800; z) Sphingosine-1 (S1 P) liase inhibitors such as LX2931; aa) Spleen tyrosine kinase (Syk) inhibitors, such as R-112; 15 bb) Protein Kinase Inhibitors (PKC) inhibitors, such as NVP-AEB071; cc) Anti-cholinergic agents such as tiotropium or aclidinium; dd) Beta adrenergic agonists such as formoterol, indacaterol or LAS100977; ee) MABA (molecules with dual activity: beta-adrenergic agonists and muscarinic receptor antagonists) ff) Histamine 1 (H1) receptor antagonists, such as azelastine or ebastine; 20 gg) Cysteinyl leukotriene (CysLT) receptor antagonists, such as montelukast; hh) Mast cell stabilizers, such as nedocromil or chromoglycate; ii) 5-lipoxygenase-activating protein (FLAP) inhibitors, such as MK886 or BAY X 1005; jj) 5-lipoxygenase (5-LO) inhibitors, such as WY-50295T; kk) Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors, such as OC-459, 25 AZD-1981, ACT-129968, QAV-680; ll) Vitamin D derivatives like calcipotriol (Daivonex) ; mm) Anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) or selective cyclooxygen- ase-2 (COX-2) inhibitors such as aceclofenac, diclofenac, ibuprofen, naproxen, apricoxib, celecoxib, cimicoxib, deracoxib, etoricoxib, lumiracoxib, parecoxib sodium, rofecoxib, selenocoxib-1 or valdecoxib; 30 nn) Anti-allergic agents; oo) Anti-viral agents; pp) Phosphodiestearase (PDE) III inhibitors; qq) Phosphosdiesterase (PDE) IV inhibitors such as roflumilast or GRC-4039; rr) Dual Phosphodiestearase (PDE) III/IV inhibitors; 35 ss) Xanthine derivatives, such as theophylline or theobromine; tt) p38 Mitogen-Activated Protein Kinase (p38 MAPK) Inhibitors such as ARRY-797; uu) Mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, such as ARRY-142886 or ARRY- 438162; vv) Janus kinase (JAK) inhibitors, such as tofacitinib (previously known as tasocitinib or CP-690,550) from Pfizer 40 and INCB-18424, from Incyte; ww) Interferons comprising Interferon beta 1 a such as Avonex from Biogen Idec, CinnoVex from CinnaGen and Rebif from EMD Serono, and Interferon beta 1b such as Betaferon from Schering and Betaseron from Berlex; xx) Interferon alpha such as Sumiferon MP; yy) Epidermal Growth Factor Receptor (EGFR) inhibitors such as erlotinib, Trastuzumab, Herceptin, Avastin, Platins 45 (cisplatin, carboplatin) or Temazolamide; zz) Antineoplastic agents such as Docetaxel, Estramustine, Anthracyc lines, (doxorubicin (Adriamycin), epirubicin (Ellence), and liposomal doxorubicin (Doxil)), Taxanes (docetaxel (Taxotere), paclitaxel (Taxol), and protein- bound paclitaxel (Abraxane)), Cyclophosphamide (Cytoxan), Capecitabine (Xeloda), 5 fluorouracil (5 FU), Gemcitabine (Gemzar) or Vinorelbine (Navelbine); 50 [0284] Specific examples of suitable corticoids and glucocorticoids that can be combined with the PI3K inhibitors of the present invention are prednisolone, methylprednisolone, dexamethasone, dexamethasone cipecilate, naflocort, de- flazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitoate, 55 tipredane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, halometasone, methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, butixocort propionate, RPR- 106541, deprodone propionate, fluticasone propionate, fluticasone furoate, halobetasol propionate, loteprednol etabo- nate, betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone,

71 EP 2 518 070 A1

betamethasone 17-valerate, betamethasone, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate and hydrocortisone probutate. [0285] Specific examples of suitable Syk kinase inhibitors that can be combined with the PI3K inhibitors of the present invention are fosfamatinib (from Rigel), R-348 (from Rigel), R-343 (from Rigel), R-112 (from Rigel), piceatannol, 2-(2- 5 Aminoethylamino)-4-[3-(trifluoromethyl)phenylamino] pyrimidine-5-carboxamide, R-091 (from Rigel), 6-[5-Fluoro- 2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-3-one ben- zenesulfonate (R-406 from Rigel), 1-(2,4,6-Trihydroxyphenyl)-2-(4-methoxyphenyl)ethan-1-one, N-[4-[6-(Cy- clobutylamino)-9H-purin-2-ylamino]phenyl]-N-methylacetamide (QAB-205 from Novartis), 2-[7-(3,4-Dimethoxyphenyl) imidazo[1,2-c]pyrimidin-5-ylamino]pyridine-3-carboxamide dihydrochloride (BAY-61-3606 from Bayer) and AVE-0950 10 (from Sanofi-Aventis). [0286] Specific examples of suitable M3 antagonists (anticholinergics) that can be combined with the PI3K inhibitors of the present invention are tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts, trospium salts, zamifenacin, revatropate, espatropate, darotropium bromide, Cl-923, NPC-14695, BEA-2108, 3-[2-Hy- droxy-2,2-bis(2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane salts (in particular aclidinium salts, 15 more preferably aclidinium bromide), 1-(2-Phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2]octane salts, 2-oxo-1,2,3,4-tetrahydroquinazoline-3-carboxylic acid endo-8- methyl-8-azabicyclo[3.2.1]oct-3-yl ester salts (DAU- 5884), 3-(4-Benzylpiperazin-1-yl)-1-cyclobutyl-1-hydroxy-1-phenylpropan-2-one (NPC-14695), N-[1-(6-Aminopyridin-2- ylmethyl)piperidin-4-yl]-2(R)-[3,3-difluoro-1 (R)-cyclopentyl]-2-hydroxy-2-phenylacetamide (J-104135), (R)-Cy- 2 clopentyl-2-hydroxy-N-[1-[4(S)-methylhexyl]piperidin-4-yl]-2-phenylacetamide (J-106366), 2(R)-Cyclopentyl-2-hydroxy- 20 N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]-2-phenylacetamide (J-104129), 1-[4-(2-Aminoethyl)piperidin-1-yl]-2(R)-[3,3- difluorocyclopent-1(R)-yl]-2-hydroxy-2-phenylethan-1-one (Banyu-280634), N-[N-[2-[N-[1-(Cyclohexylmethyl)piperidin- 3(R)-ylmethyl]carbamoyl]ethyl]carbamoylmethyl]-3,3,3-triphenylpropionamide (Banyu CPTP), 2(R)-Cyclopentyl-2-hydroxy-2-phenylacetic acid 4-(3-azabicyclo[3.1.0]hex-3-yl)-2-butynyl ester (Ranbaxy 364057), 3(R)-[4,4-Bis(4-fluorophenyl)-2-oxoimidazolidin-1-yl]-1-methyl-1-[2-oxo-2-(3-thienyl)ethyl]pyrrolidinium iodide, N-[1-(3-Hydroxybenzyl)-1-meth- 25 ylpiperidinium-3(S)-yl]-N-[N-[4-(isopropoxycarbonyl)phenyl]carbamoyl]-L-tyrosinamide trifluoroacetate, UCB-101333, Merck’s OrM3, 7-endo-(2-hydroxy-2,2-diphenylacetoxy)-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0(2,4)]nonane salts, 3(R)-[4,4-Bis(4-fluorophenyl)-2-oxoimidazolidin-1-yl]-1-methyl-1-(2-phenylethyl)pyrrolidinium iodide, trans-4-[2-[Hy- droxy-2,2-(dithien-2-yl)acetoxy]-1-methyl-1-(2-phenoxyethyl)piperidinium bromide fromNovartis (412682), 7-(2,2- diphe- nylpropionyloxy)-7,9,9-trimethyl-3-oxa-9-azoniatricyclo[3.3.1.0*2,4*]nonane salts, 7-hydroxy-7,9,9-trimethyl-3-oxa-9- 30 azoniatricyclo[3.3.1.0*2,4*]nonane 9-methyl-9H-fluorene-9-carboxylic acid ester salts, all of them optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally in the form of their pharmacologically-compatible acid addition salts. Among the salts chlorides, bromides, iodides and methanesulphonates are preferred. [0287] Specific examples of suitable beta adrenergic agonists β(2-agonists) that can be combined with the PI3K 35 inhibitors of the present invention are are terbutaline sulphate, eformoterol fumarate, formoterol fumarate, bambuterol, ibuterol, isoprenaline hydrochloride, dopexamine, metaprotenerol, tulobuterol, procaterol hydrochloride, sibenadet hydrochloride, mabuterol hydrochloride, albuterol sulphate, salbutamol sulphate, salmefamol, salmeterol xinafoate, carmoterol hydrochloride, (R)-albuterol hydrochloride, Levalbuterol hydrochloride; Levosalbutamol hydrochloride; (-)-Salb- utamol hydrochloride, formoterol, (R,R)-Formoterol tartrate; Arformoterol tartrate, sulfonterol, Bedoradrine sulphate, 40 Indacaterol, Trantinterol hydrochloride, Milveterol hydrochloride, Olodaterol, fenoterol hydrobromide, rimoterol hydrobromide, riproterol hydrochloride, Vilanterol broxaterol, pirbuterol hydrochloride, bitolterol mesylate, clenbuterol hydrochloride, AZD-3199, GSK-159802; GSK-597901, GSK-678007, GSK-961081; 4-[2-[3-(1H-Benzimidazol-1-yl)-1,1- dimethylpropylamino]-1-hydroxyethyl]-2-(4-methoxybenzylamino)phenol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin- 8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin- 45 8-yl]-2-[3-(4-domethoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]- 2-[3-(4-n-butyloxyhenyl)-2-methyl-2-propylamino]ethanol, KUL-1248, HOKU- 81, SM-110444, RP-58802B, LAS 100977 and compounds described in PCT patent applications Nos. WO 2007/124898, WO 2006/122788A1, WO 2008/046598, WO 2008095720, WO 2009/068177 and WO 2010/072354. [0288] Specific examples of suitable anti-allergic agents that can be combined with the PI3K inhibitors of the present 50 invention are anti-histamines (e.g. Methapyrilene, Mequitazine, Azelastine hydrochloride, Acrivastine, Emedastine di- fumarate, Emedastine fumarate, Loratadine, Cyproheptadine hydrochloride, Diphenhydramine hydrochloride, Doxepin hydrochloride, Promethazine hydrochloride, Levocabastine hydrochloride, Desloratadine, Cinnarizine, Setastine hydrochloride, Mizolastine, Ebastine, Cetirizine hydrochloride, Epinastine hydrochloride, Olopatadine hydrochloride, Bepotas- tine besilate,Triprolidine hydrochloride, Rupatadine fumarate, Fexofenadine hydrochloride, Levocetirizine dihydrochlo- 55 ride, Ketotifen, Azatadine maleate, Dimethindene maleate, Clemastine fumarate, Alcaftadine, Bilastine, Vapitadine hydrochloride, AZD-1744, GSK-1 004723D, GSK-835726 or SUN-1334H. [0289] Specific examples of suitable Phosphosdiesterase IV (PDE IV) inhibitors that can be combined with the PI3K inhibitors of the present invention are benafentrine dimaleate, etazolate, denbufylline, rolipram, cipamfylline, zardaverine,

72 EP 2 518 070 A1

arofylline, filaminast, tipelukast, tofimilast, piclamilast, tolafentrine, mesopram, drotaverine hydrochloride, lirimilast, roflumilast, cilomilast, oglemilast, apremilast, tetomilast, filaminast, (R)-(+)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2- phenylethyl]pyridine (CDP-840), N-(3,5-Dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoa- cetamide (GSK-842470), 9-(2-Fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine (NCS-613), N-(3,5-Dichloro-4-pyrid- 5 inyl)-8-methoxyquinoline-5-carboxamide (D-4418), 3-[3-(Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopro- pyl-3H-purine hydrochloride (V-11294A), 6-[3-(N,N-Dimethylcarbamoyl)phenylsulfonyl]-4-(3-methoxyphenylamino)-8- methylquinoline-3-carboxamide hydrochloride (GSK-256066), 4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]- 1-(2-methoxyethyl)pyridin-2(1H)-one (T-440), (-)-trans-2-[3’-[3-(N-Cyclopropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naph- thyridin-1-yl]-3-fluorobiphenyl-4-yl]cyclopropanecarboxylic acid, MK-0873, CDC-801, UK-500001, BLX-914, 2-car- 10 bomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluroromethoxyphenyl)cyclohexan1-one, cis [4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol, 5(S)-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3(S)-(3-methylben- zyl)piperidin-2-one (IPL-455903), ONO-6126 (Eur Respir J 2003, 22 (Suppl. 45): Abst 2557) and the compounds claimed in the PCT patent applications number WO 03/097613, WO 2004/058729, WO 2005/049581, WO 2005/123693, WO 2005/123692, and WO 2010/069504. 15 [0290] Specific examples of suitable immunosupressants that can be combined with the PI3K inhibitors of the present invention are picremolimus, tacrolimus, cyclosporine A, leflunomide, teriflunomide, vidofludimus, laquinimod, methotrexate, 5-fluorouracil (5-FU), anti- TNF agents and compounds described in PCT patent applications Nos. WO 2008/077639, WO 2009/021696, WO 2009/153043, and WO2010083975 (in particular amino(iso)nicotinic acid derivatives selected from the group consisting of 2-(3’-ethoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid, 2-(3,5-difluoro-3’-meth- 20 oxybiphenyl-4-ylamino)nicotinic acid and 2-(3,5-difluoro-2-methylbiphenyl-4-ylamino)nicotinic acid; and azabiphenylaminobenzoic acid derivatives selected from the group consisting of 5-cyclopropyl- 2-(2-(2,6-difluorophenyl)pyrimidin- 5-ylamino)benzoic acid, 5-cyclopropyl-2-((2-(2-(trifluoromethyl)phenyl)pyrimidin-5-yl)amino)benzoic acid and 5-methyl- 2-((6-(2,3-difluorophenyl)pyridin-3-yl)amino)benzoic acid) [0291] Specific examples of suitable anti-infectives that can be combined with the PI3K inhibitors of the present 25 invention are aclarubicin, actinomycin D, amrubicin, annamycin, adhamycin, bleomycin, daunorubicin, doxorubicin, el- samitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, mupiricin, nemorubicin, neocarzinostatin, peplomycin, pira- rubicin, rebeccamycin, retapamulin, stimalamer, streptozocin, valrubicin, zinostatin, amphotericin B, bifonazole, caspo- fungin, clotrimazole, echinocandin B, econazole, fluconazole, flucytosine, itraconazole, ketoconazole, miconazole, posa- conazole, ravuconazole, terbinafine, tioconazole, voriconazole and combinations thereof. 30 [0292] Particularly preferred combination products according to the invention comprise a compound of formula (I) and a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of mometasone furoate, ciclesonide, budesonide, fluticasone propionate, fluticasone furoate, betamethasone valerate, clobetasol propionate, tiotropium salts, glycopyrronium salts, 3-[2-Hydroxy-2,2-bis (2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane salts (in particular aclidinium salts, preferably aclidinium bromide), 1-(2-Phenylethyl)- 35 3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2]octane salts, formoterol, salmeterol, indacaterol, carmoterol, LAS 100977, compounds described in PCT patent applications Nos. WO 2008/077639, WO 2009/021696, WO 2009/153043, and WO 2010/083975 (in particular amino(iso)nicotinic acid derivatives selected from the group consisting of 2-(3’- ethoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid, 2-(3,5- difluoro-3’-methoxybiphenyl-4-ylamino)nicotinic acid and 2-(3,5- difluoro-2-methylbiphenyl-4-ylamino)nicotinic acid; and azabiphenylaminobenzoic acid derivatives selected 40 from the group consisting of 5-cyclopropyl-2-(2-(2,6-difluorophenyl)pyrimidin-5-ylamino)benzoic acid, 5-cyclopropyl- 2-((2-(2-(trifluoromethyl)phenyl)pyrimidin-5-yl)amino)benzoic acid and 5-methyl-2-((6-(2,3-difluorophenyl)pyridin-3-yl) amino)benzoic acid), methapyrilene, cetirizine, loratadine, ebastine, desloratadine, fexofenadine, azelastine, levocabastine, olopatadine, Montelukast, picremolimus, tacrolimus, mupiricin, retapamulin, clotrimazole, ketoconazole and terbinafine. 45 [0293] The compounds of formula (I) and the combinations of the invention may be used in the treatment of respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo- dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and hematologic malignancies, leukemia, 50 lymphomas and solid tumors, wherein the use of a PI3K inhibitor is expected to have a beneficial effect, for example leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis. 55 [0294] The active compounds in the combination product may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route. [0295] It is contemplated that all active agents would be administered at the same time, or very close in time. Alter-

73 EP 2 518 070 A1

natively, one or two actives could be administered in the morning and the other (s) later in the day. Or in another scenario, one or two actives could be administered twice daily and the other (s) once daily, either at the same time as one of the twice-a-day dosing occurred, or separately. Preferably at least two, and more preferably all, of the actives would be administered together at the same time. 5 [0296] Preferably, at least two, and more preferably all actives would be administered as an admixture. [0297] The invention is also directed to a combination product of the compounds of the invention together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3- Kinases (PI3Ks), in particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and 10 neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo- dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s 15 disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis. [0298] The invention also encompasses the use of a combination of the compounds of the invention together with one or more other therapeutic agents for the manufacture of a formulation or medicament for treating these diseases. 20 [0299] The invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloprolif- 25 erative disorders (MPDs such as polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic 30 rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis; comprising administering a therapeutically effective amount of a combination of the compounds of the invention together with one or more other therapeutic agents. [0300] The active compounds in the combinations of the invention may be administered by any suitable route, depending on the nature of the disorder to be treated, e.g. orally (as syrups, tablets, capsules, lozenges, controlled- release 35 preparations, fast-dissolving preparations, etc); topically (as creams, ointments, lotions, nasal sprays or aerosols, etc); by injection (subcutaneous, intradermic, intramuscular, intravenous, etc.) or by inhalation (as a dry powder, a solution, a dispersion, etc). [0301] The active compounds in the combination, i.e. the pyrrolotriazinone derivatives of the invention, and the other optional active compounds may be administered together in the same pharmaceutical composition or in different com- 40 positions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route. [0302] One execution of the present invention consists of a kit of parts comprising a pyrrolotriazinone derivative of the invention together with instructions for simultaneous, concurrent, separate or sequential use in combination with another active compound useful in the treatment of respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine 45 function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo- dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particularwherein thepathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic 50 anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis. [0303] Another execution of the present invention consists of a package comprising a pyrrolotriazinone derivative of the invention and another active compound useful in the treatment of respiratory diseases; allergic diseases; inflammatory 55 or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in

74 EP 2 518 070 A1

particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, pso- 5 riasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis.

Pharmaceutical Compositions

[0304] Pharmaceutical compositions according to the present invention comprise the compounds of the invention in 10 association with a pharmaceutically acceptable diluent or carrier. [0305] As used herein, the term pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers, deuterated derivatives thereof or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a com- 15 pound to an organism. [0306] As used herein, a physiologically/pharmaceutically acceptable diluent or carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. [0307] The invention further provides pharmaceutical compositions comprising the compounds of the invention in 20 association with a pharmaceutically acceptable diluent or carrier together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), such as the ones previously described. [0308] The invention is also directed to pharmaceutical compositions of the invention for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide Kinases3- (PI3Ks), in 25 particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune- mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in 30 particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis. The invention also encompasses the use 35 of a pharmaceutical composition of the invention for the manufacture of a medicament for treating these diseases. [0309] The invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; 40 neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I dia- 45 betes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis; comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention. [0310] The present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at 50 least a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise 0.001 % to 99% by weight, preferably 0.01% to 90% by weight, of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application. Preferably the compositions are made up in a form suitable for oral, inhalation, topical, nasal, rectal, percutaneous or injectable administration. 55 [0311] Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.

75 EP 2 518 070 A1

[0312] The pharmaceutically acceptable excipients which are admixed with the active compound or salts of such compound, to form the compositions of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administering the compositions. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and 5 polyethylene glycols. [0313] Additional suitable carriers for formulations of the compounds of the present invention can be found in Rem- ington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.

i) Oral Administration 10 [0314] The compounds of the invention may be administered orally (peroral administration;per os (latin)). Oral administration involve swallowing, so that the compound is absorbed from the gut and delivered to the liver via the portal circulation (hepatic first pass metabolism) and finally enters the gastrointestinal (GI) tract. [0315] Compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules, 15 inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as mixtures, solutions, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well- known in the art. The active ingredient may also be presented as a bolus, electuary or paste. [0316] Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, talc, gelatine, acacia, stearic acid, 20 starch, lactose and sucrose. [0317] A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Com- pressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. 25 [0318] Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound mois- tened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. [0319] For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. 30 Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl- substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form. [0320] Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include micro- 35 crystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, 40 surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet. [0321] Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. Other conventional ingredients include 45 anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents. [0322] Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may 50 include one or more layers and may be coated or uncoated; or encapsulated. [0323] The formulation of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1 ", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., 1980. [0324] Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatine capsule. Where the composition is in the form of a soft gelatine capsule any 55 pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatine capsule. [0325] Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

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[0326] Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their entireties. 5 [0327] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise an insoluble active compound of the invention or a pharmaceutically 10 acceptable salt thereof in association with water, together with a suspending agent or flavouring agent. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

ii) Oral mucosal administration

15 [0328] The compounds of the invention can also be administered via the oral mucosal. Within the oral mucosal cavity, delivery of drugs is classified into three categories: (a) sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, (b) buccal delivery, which is drug administration through the mucosal membranes lining the cheeks (buccal mucosa), and (c) local delivery, which is drug delivery into the oral cavity. Pharmaceutical products to be administered via the oral mucosal can be designed using mucoadhesive, quick dissolve 20 tablets and solid lozenge formulations, which are formulated with one or more mucoadhesive (bioadhesive) polymers (such as hydroxy propyl cellulose, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, polyvinyl alcohol, polyisobutylene or polyisoprene); and oral mucosal permeation enhancers (such as butanol, butyric acid, propranolol, sodium lauryl sulphate and others)

25 iii) Inhaled administration

[0329] The compounds of the invention can also be administered by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pres- 30 surized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1 ,1,2-tetrafluoroethane or 1 ,1,1,2,3,3,3- heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin. [0330] Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules 35 and cartridges of for example gelatine or blisters of for example laminated aluminium foil, for use in an inhaler or insufflato r. Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier substance) such as lactose or starch. Use of lactose is preferred. Each capsule or cartridge may generally contain between 0.001-50 mg, more preferably 0.01-5 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof. Alternatively, the active ingredient (s) may be presented without excipients. 40 [0331] Packaging of the formulation may be suitable for unit dose or multi-dose delivery. In the case of multi- dose delivery, the formulation can be pre-metered or metered in use. Dry powder inhalers are thus classified into three groups: (a) single dose, (b) multiple unit dose and (c) multi dose devices. [0332] For inhalers of the first type, single doses have been weighed by the manufacturer into small containers, which are mostly hard gelatine capsules. A capsule has to be taken from a separate box or container and inserted into a 45 receptacle area of the inhaler. Next, the capsule has to be opened or perforated with pins or cutting blades in order to allow part of the inspiratory air stream to pass through the capsule for powder entrainment or to discharge the powder from the capsule through these perforations by means of centrifugal force during inhalation. After inhalation, the emptied capsule has to be removed from the inhaler again. Mostly, disassembling of the inhaler is necessary for inserting and removing the capsule, which is an operation that can be difficult and burdensome for some patients. 50 [0333] Other drawbacks related to the use of hard gelatine capsules for inhalation powders are (a) poor protection against moisture uptake from the ambient air, (b) problems with opening or perforation after the capsules have been exposed previously to extreme relative humidity, which causes fragmentation or indenture, and (c) possible inhalation of capsule fragments. Moreover, for a number of capsule inhalers, incomplete expulsion has been reported (e. g. Nielsen et al, 1997). 55 [0334] Some capsule inhalers have a magazine from which individual capsules can be transferred to a receiving chamber, in which perforation and emptying takes place, as described in WO 92/03175. Other capsule inhalers have revolving magazines with capsule chambers that can be brought in line with the air conduit for dose discharge (e. g. WO91/02558 and GB 2242134). They comprise the type of multiple unit dose inhalers together with blister inhalers,

77 EP 2 518 070 A1

which have a limited number of unit doses in supply on a disk or on a strip. [0335] Blister inhalers provide better moisture protection of the medicament than capsule inhalers. Access to the powder is obtained by perforating the cover as well as the blister foil, or by peeling off the cover foil. When a blister strip is used instead of a disk, the number of doses can be increased, but it is inconvenient for the patient to replace an empty 5 strip. Therefore, such devices are often disposable with the incorporated dose system, including the technique used to transport the strip and open the blister pockets. [0336] Multi-dose inhalers do not contain pre- measured quantities of the powder formulation. They consist of a relatively large container and a dose measuring principle that has to be operated by the patient. The container bears multiple doses that are isolated individually from the bulk of powder by volumetric displacement. Various dose measuring principles 10 exist, including rotatable membranes (Ex. EP0069715) or disks (Ex. GB 2041763; EP 0424790; DE 4239402 and EP 0674533), rotatable cylinders (Ex. EP 0166294; GB 2165159 and WO 92/09322) and rotatable frustums (Ex. WO 92/00771), all having cavities which have to be filled with powder from the container. Other multi dose devices have measuring slides (Ex. US 5201308 and WO 97/00703) or measuring plungers with a local or circumferential recess to displace a certain volume of powder from the container to a delivery chamber or an air conduit (Ex. EP 0505321, WO 15 92/04068 and WO 92/04928), or measuring slides such as the Genuair® (formerly known as Novolizer SD2FL), which is described the following patent applications Nos: WO97/000703, WO03/000325 and WO2006/008027. [0337] Reproducible dose measuring is one of the major concerns for multi dose inhaler devices. [0338] The powder formulation has to exhibit good and stable flow properties, because filling of the dose measuring cups or cavities is mostly under the influence of the force of gravity. 20 [0339] For reloaded single dose and multiple unit dose inhalers, the dose measuring accuracy and reproducibility can be guaranteed by the manufacturer. Multi dose inhalers on the other hand, can contain a much higher number of doses, whereas the number of handlings to prime a dose is generally lower. [0340] Because the inspiratory air stream in multi-dose devices is often straight across the dose measuring cavity, and because the massive and rigid dose measuring systems of multi dose inhalers can not be agitated by this inspiratory 25 air stream, the powder mass is simply entrained from the cavity and little de- agglomeration is obtained during discharge. [0341] Consequently, separate disintegration means are necessary. However in practice, they are not always part of the inhaler design. Because of the high number of doses in multi-dose devices, powder adhesion onto the inner walls of the air conduits and the de-agglomeration means must be minimized and/or regular cleaning of these parts must be possible, without affecting the residual doses in the device. Some multi dose inhalers have disposable drug containers 30 that can be replaced after the prescribed number of doses has been taken (Ex. WO 97/000703). For such semi-permanent multi dose inhalers with disposable drug containers, the requirements to prevent drug accumulation are even more strict. [0342] Apart from applications through dry powder inhalers the compositions of the invention can be administered in aerosols which operate via propellant gases or by means of socalled atomisers, via which solutions of pharmacologically- active substances can be sprayed under high pressure so that a mist of inhalable particles results. The advantage of 35 these atomisers is that the use of propellant gases can be completely dispensed with. Such atomiser is the Respimat® which is described, for example, in PCT Patent Applications Nos. WO 91/14468 and WO 97/12687, reference here is being made to the contents thereof. [0343] Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use 40 of a suitable liquefied propellant. Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the active ingredient (s) and a suitable propellant such as a fluorocarbon or hydrogen- containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e. g. dichlorodifluoromethane, trichlorofluor- omethane, dichlorotetra-fluoroethane, especially 1,1, 1, 2-tetrafluoroethane, 1,1, 1,2, 3,3, 3-heptafluoro-n-propane or a mixture thereof. Carbon dioxide or other suitable gas may also be used as propellant. 45 [0344] The aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants (eg oleic acid or lecithin) and cosolvens (eg ethanol). Pressurised formulations will generally be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece. [0345] Medicaments for administration by inhalation desirably have a controlled particle size. The optimum particle 50 size for inhalation into the bronchial system is usually 1-10 Pm, preferably 2-5 Pm. Particles having a size above 20 Pm are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of the active ingredient as produced may be size reduced by conventional means eg by micronisation. The desired fraction may be separated out by air classification or sieving. Preferably, the particles will be crystalline. [0346] Achieving high dose reproducibility with micronised powders is difficult because of their poor flowability and 55 extreme agglomeration tendency. To improve the efficiency of dry powder compositions, the particles should be large while in the inhaler, but small when discharged into the respiratory tract. Thus, an excipient such as lactose or glucose is generally employed. The particle size of the excipient will usually be much greater than the inhaled medicament within the present invention. When the excipient is lactose it will typically be present as milled lactose, preferably crystalline

78 EP 2 518 070 A1

alpha lactose monohydrate. Pressurized aerosol compositions will generally be filled into canisters fitted with a valve, especially a metering valve. Canisters may optionally be coated with a plastics material e. g. a fluorocarbon polymer as described in W096/32150. Canisters will be fitted into an actuator adapted for buccal delivery. 5 iv) Nasal mucosal administration

[0347] The compounds of the invention may also be administered via the nasal mucosal. Typical compositions for nasal mucosa administration are typically applied by a metering, atomizing spray pump and are in the form of a solution 10 or suspension in an inert vehicle such as water optionally in combination with conventional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents.

v) Parenteral Administration

15 [0348] The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrath- ecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle- free injectors and infusion techniques. [0349] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohy- 20 drates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. [0350] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of 25 compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. [0351] Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi- solid, or thixotropic liquid for administration as an implanted 30 depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.

vi) Topical Administration

35 [0352] The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Li- posomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J 40 Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection. [0353] Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

45 vii) Rectal/Intravaginal Administration

[0354] Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified 50 release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

viii) Ocular Administration

[0355] Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops 55 of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable {e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxy-

79 EP 2 518 070 A1

propylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. [0356] Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Mod- 5 ified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.

ix) Other Technologies

[0357] Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and 10 suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration. The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is typically in the range of 0.01-3000 mg, more preferably 0.5-1000 mg of active 15 ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof per day. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day. [0358] Preferably, the the pharmaceutical compositions of the invention are made up in a form suitable for oral, inhalation or topical administration, being particularly preferred oral or inhalation administration. [0359] The pharmaceutical formulations may conveniently be presented in unit dosage form and may be prepared by 20 any of the methods well known in the art of pharmacy. Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose. [0360] The amount of each active which is required to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under treatment, and the particular disorder or disease being treated. [0361] The following preparations forms are cited as formulation examples: 25 Formulation Examples

Formulation Example 1 (Oral suspension)

30 [0362]

Ingredient Amount Active Compound 3 mg 35 Citric acid 0,5 g Sodium chloride 2,0 g Methyl paraben 0,1 g Granulated sugar 25 g 40 Sorbitol (70% solution) 11 g Veegum K 1,0 g Flavoring 0,02 g 45 Dye 0,5 mg Distilled water q.s. to 100 mL

Formulation Example 2 (Hard gelatine capsule for oral administration) 50 [0363]

Ingredient Amount

55 Active Compound 1 mg Lactose 150 mg Magnesium stearate 3 mg

80 EP 2 518 070 A1

Formulation Example 3 (Gelatin cartridge for inhalation)

[0364]

5 Ingredient Amount Active Compound (micronized) 0,2 mg Lactose 25 mg

10 Formulation Example 4 (Formulation for inhalation with a DPI)

[0365]

15 Ingredient Amount Active Compound (micronized) 15 mg Lactose 3000 mg

20 Formulation Example 5 (Formulation for a MDI)

[0366]

25 Ingredient Amount Active Compound (micronized) 10g 1,1,1,2,3,3,3-heptafluoro-n-propane q.s. to 200 mL

30 [0367] In all the formulation examples, active compound is (S)-2-(1-(2- amino-9H-purin-6-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one. [0368] Modifications, which do not affect, alter, change or modify the essential aspects of the compounds, combinations or pharmaceutical compositions described, are included within the scope of the present invention.

35 Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof: 40

45

50

55

wherein,

81 EP 2 518 070 A1

X represents a nitrogen atom or a -CR6 group; n represents 0, 1, 2 or 3; Ra and R b each independently represent a hydrogen atom, a C 1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group; 5 R1 represents a linear or branched C1-C4 alkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-C14 aryl group, a 5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 14- membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted 10 by one or more substituents selected from a halogen atom, a hydroxy group, a cyano group, a linear or branched C1-C4 alkyl group, a C 1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group, a C 3-C4 cycloalkyl group, a -(CH 2)1-3CN group, a -(CH2) 0-3OR8 group, a -(CH 2)0-3NR7R8 group, a -C (O)-(CH2)1-3-CN group, a -C (O)-(CH2)0-3-R8 group, a -C(O)-(CH2)0-3-NR7R8 group, a -S(O)2(CH2)0-3R8 group or a -S(O)2(CH2)0-3NR7R8 group; R2 and R3 each independently represent a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, 15 a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -NR’R" group, or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C7 cycloalkyl group; R4 represents a hydrogen atom, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH 2)1-4NR’R" group, or a linear or branched C 1-C4 alkyl group, which alkyl group 20 is unsubstituted or substituted by one or more substituents selected from a C 1-C4 alkoxy group, a cyano group, a C3-C4 cycloalkyl group, a -C(O)-(CH2)0-3-R’ group or a -C(O)-(CH2)0-3-NR’R" group; R6 represents a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a 1C-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents 25 selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; R7 and R 8 each independently represent a hydrogen atom, a C 1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C1-C4 alkoxy group or a linear 30 or branched C1-C4 alkyl group. R5 represents a group selected from:

i) a group of formula (IIa)

35

40

45

ii) a group of formula (IIb)

50

55

82 EP 2 518 070 A1

and iii) a group of formula (IIc)

5

10 wherein

Y represents a linker selected from a -NR’- group, -O- or -S-; wherein R’ is as defined above; (*) represents where R 5 is bonded to the carbon atom attached to R 4 and to the pyrrolotriazinone group; 15 W1 represents a -CR11 group and W2 represents a nitrogen atom, or W1 represents a nitrogen atom and W2 represents a -CR12 group; G1 represents a -CR14 group and G2 represents a nitrogen atom, or G1 represents a nitrogen atom and G2 represents a -CR15 group, or G1 represents a -CR14 group and G2 represents a -CR15 group; G3 represents a nitrogen atom or a -CR16 group; 20 R9, R10, R11, R12, R13, R14, R15 and R16 each independently represent a hydrogen atom, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a 1 C-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3CN group, a -C(O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C(O)-(CH2)0-3-NR’R", a -(CH2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a 25 C3-C4 cycloalkyl group; wherein R’ and R" are as defined above; R17 represents a group selected from

a) a group of formula (IIIa),

30

35

40

b) a group of formula (IIIb),

45

50

55 c) a group of formula (IIIc), and

83 EP 2 518 070 A1

5

10

d) a group of formula (IIId), 15

20

25

wherein 30

G4 represents a nitrogen atom or a -CR22 group; G5 and G6 each independently represents a nitrogen atom or a carbon atom, wherein when one of G5 and G6 represents a nitrogen atom the remaining represents a carbon atom; G7 represents a -NH group or a -CH group; 35 G8 represents a nitrogen atom or a -CR23 group; G9 represents a nitrogen atom or a -CR24 group; G10 represents a nitrogen atom or a -CR25 group; G11 represents a nitrogen atom or a -CR26 group; G12 represents a nitrogen atom or a -CR27 group; 40 G13 represents a nitrogen atom or a -CR28 group; G14 and G 15 each independently represents a nitrogen atom or a -carbon atom, wherein when one of G14 and G15 represents a nitrogen atom the remaining represents a carbon atom; G16 represents a -NH group or a -CH group; G17 represents a nitrogen atom or a -CR29 group; 45 G18 represents a nitrogen atom or a -CR30 group; R18, R 19 R 20, R 21, R 22, R 23, R 24, R 25, R 26, R 27, R 28, R 29, and R 30 each independently represent a hydrogen atom, a C 1-C4 alkoxy group, a C 1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3CN group, a (O)-(CH -C 2)1-3-CN group, a -C (O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R"group, or a linear or branched 50 C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" are as defined above; and wherein Y is as defined above;

or in the case that Y represents a -NR’- group, R 4 together with the -NR’- group and the carbon atom to which both 55 R4 and the -NR’- group are bonded form a 4- to 7-membered, saturated N-containing heterocyclyl group, which heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group.

84 EP 2 518 070 A1

2. A compound according to claim 1, wherein

Ra and Rb each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group; n represents 0, 1 or 2; 5 R1 represents a linear or branched C1-C4 alkyl group, a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered monocyclic or bicyclic heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group or a morpholinyl group; wherein the cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl or morpholinyl 10 groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3OR8 group, a -(CH2)0-3NR7R8 group, a -C(O)-(CH2)-0 3-R8 group or a -C(O)-(CH2)0-3-NR7R8 group; wherein R7 and R8 each independently represent a hydrogen atom or a C1-C4 alkyl group; R2 represents a hydrogen atom, a halogen atom, a hydroxy group, a C1-C3 alkoxy group, a C1-C3 haloalkyl 15 group, a C3-C4 cycloalkyl group, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; R3 represents a hydrogen atom, a halogen atom, a hydroxy group, a C1-C3 alkoxy group, a C1-C3 haloalkyl group, a C3-C4 cycloalkyl group, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; 20 R4 represents a hydrogen atom, a C1-C3 alkoxy group, a C1-C3 haloalkyl group, a C3-C4 cycloalkyl group, or a linear or branched C1-C3 alkyl group; R6 represents a hydrogen atom, a halogen atom, a 1C-C3 alkoxy group, a C1-C3 haloalkyl group, a C3-C4 cycloalkyl group, a -NH 2 group, a -N (CH3)H group, a -N (CH3)2 group, or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; 25 R5 represents a moiety of formula (II-a2), (IIb-1), (IIB-2) or (Illa-1):

30

35

wherein: 40

$ R9, R10, and R12 each independently represent a hydrogen atom, a 2) -(CH0-3CN group, a -C (O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C(O)-(CH2)0-3-NR’R", a -(CH2)0-3NR’R" group, or a linear or branched C1-C4 alkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C1-C4 alkoxy group or a linear or branched C1-C4 alkyl group; 45 $ R13, R14, R15 and R16 each independently represent a hydrogen atom, a -(CH2)0-3CN group, a -C (O)-(CH2)0-3-NR’R" or a -(CH 2)0-3NR’R" group; wherein R’ and R" each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group; $ R18 and R23 each independently represent a hydrogen atom, a -(CH 2)0-3CN group, a -C(O)-(CH2)1-3-CN group, a -C (O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R" group, or a linear or branched 50 C1-C4 alkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C1-C4 alkoxy group or a linear or branched C1-C4 alkyl group $ Y represents a -NR’- group, -O- or -S-; wherein R’ represents hydrogen or a linear or branched C1-C4 alkyl group; or in the case that Y represents a -NR’-group, R 4 together with the -NR’- group and the carbon atom to which both R4 and the -NR’- group are bonded form a 4- to 7- membered, saturated N-containing 55 heterocyclyl group

3. A compound according to claim 1, wherein R1 represents a C1-C3 alkyl group, a C3-C7 cycloalkyl group, a phenyl group, a naphthyl group, a 5- to 10- membered monocyclic or bicyclic heteroaryl group containing containing one,

85 EP 2 518 070 A1

two or three heteroatoms selected from O, S and N, or a 5- to 10- membered monocyclic or bicyclic heterocyclyl group containing containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, phenyl, naphthyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxy group, a cyano group, a linear or branched C1-C4 5 alkyl group, a C1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH 2)0-3OR8 group, a -(CH2)0-3NR7R8 group, a -C(O)-(CH2)0-3-R8 group or a -C(O)-(CH2)0-3-NR7R8 group; wherein R7 and R8 are as defined in claim 1.

4. A compound according to claim 3, wherein R1 represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- 10 membered monocyclic or bicyclic heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group or a morpholinyl group, wherein the cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl or morpholinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or 15 branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3OR8 group, a -(CH2)0-3NR7R8 group, a -C(O)-(CH2)0-3-R8 group or a -C(O)-(CH2)0-3-NR7R8 group; wherein R7 and R8 each independently represent a hydrogen atom or a C1-C4 alkyl group; and 20 wherein R1 preferably represents a phenyl group or a pyridinyl group, which phenyl or pyridinyl is unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a linear or branched C 1-C3 alkyl group or a -(CH2)0-3OCH3 group; and wherein preferably said phenyl and pyridinyl groups are directly bonded to the pyrrolotriazinone group.

25 5. A compound according to any one of claims 1, 3 or 4, wherein R2 represents a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a C 1-C4 alkoxy group, a C 1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group, a C 3-C4 cycloalkyl group, a -(CH 2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C 1-C3 alkoxy group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, or a linear or branched C1-C3 alkyl group; 30 and wherein R2 preferably represents a hydrogen atom, a halogen atom, a hydroxy group, a 1C-C3 alkoxy group, a C1-C3 haloalkyl group, a C 3-C4 cycloalkyl group, a -NH 2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group.

35 6. A compound according to any one of claims 1 or 3 to 5, wherein R3 represents a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3NR’R" group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C 1-C3 alkoxy group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, or a linear or branched C1-C3 alkyl group; 40 and wherein R3 preferably represents a hydrogen atom, a halogen atom, a hydroxy group, a 1C-C3 alkoxy group, a C1-C3 haloalkyl group, a C 3-C4 cycloalkyl group, a -NH 2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group.

45 7. A compound according to any one of claims 1 or 3 to 6, wherein R4 represents a hydrogen atom, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)1-4NR’R" group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C3 alkoxy group, a -C(O)-(CH2)0-3-R’ group or a -C(O)-(CH2)0-3-NR’R" group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, or a linear or branched C1-C3 alkyl group; 50 and wherein R4 preferably represents a hydrogen atom, a C 1-C3 alkoxy group, a C 1-C3 haloalkyl group, a C 3-C4 cycloalkyl group, or a linear or branched C1-C3 alkyl group.

8. A compound according to any one of claims 1 or 3 to 7, wherein R6 represents a hydrogen atom, a halogen atom, 55 a hydroxy group, a cyano group, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -(CH2)0-3NR’R" group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C 1-C3 alkoxy group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, or a linear or branched C1-C3 alkyl group;

86 EP 2 518 070 A1

and wherein R6 preferably represents a hydrogen atom, a halogen atom, a C 1-C3 alkoxy group, a C 1-C3 haloalkyl group, a C3-C4 cycloalkyl group, a -NH2 group, a -N(CH3)H group, a -N(CH3)2 group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group. 5

9. A compound according to any one of claims 1 or 3 to 8, wherein R5 represents a group selected from

i) a group of formula (IIa-1), and

10

15

20

ii) a group of formula (IIa-2)

25

30

35 wherein

R9, R10, R11 and R12 each independently represent a hydrogen atom, a C 1-C4 alkoxy group, a C1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group, a C 3-C4 cycloalkyl group, a -(CH 2)0-3CN group, a -C (O)-(CH2)1-3-CN group, 40 a -C(O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a1 -CC4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C1-C4 alkoxy group or a linear or branched C1-C4 alkyl group.

45 10. A compound according to any one of claims 1 or 3 to 8, wherein R5 represents a group selected from

i) a group of formula (IIb-1),

50

55

87 EP 2 518 070 A1

5

10

ii) a group of formula (IIb-2),

15

20

25

iii) a group of formula (IIb-3),

30

35

40 iv) a group of formula (IIb-4), and

45

50

v) a group of formula (IIb-5),

55

88 EP 2 518 070 A1

5

10

wherein

R13, R14, R15 and R 16 each independently represent a hydrogen atom, a C 1-C4 alkoxy group, a C 1-C4 haloalkyl 15 group, a C 1-C4 hydroxyalkyl group, a C 3-C4 cycloalkyl group, a -(CH 2)0-3CN group, a -C (O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a1 -CC4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C 1-C4 alkoxy group or a linear or branched C 1-C4 alkyl group; and wherein 20 Y is as defined in claim 1; or in the case that Y represents a -NR’- group, R 4 together with the -NR’- group and the carbon atom to which both R4 and the -NR’- group are bonded form a 4- to 7-membered, saturated N- containing heterocyclyl group, which heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group. 25

11. A compound according to any one of claims 1 or 3 to 8, wherein R5 represents a group selected from

i) a group of formula (IIIa-1),

30

35

40 ii) a group of formula (IIIa-2),

45

50

iii) a group of formula (IIIa-3),

55

89 EP 2 518 070 A1

5

10 iv) a group of formula (IIIa-4),

15

20

v) a group of formula (IIIa-5),

25

30

35 vi) a group of formula (IIIa-6),

40

45

vii) a group of formula (IIIa-7),

50

55

90 EP 2 518 070 A1

viii) a group of formula (IIIa-8),

5

10

ix) a group of formula (IIIa-9), 15

20

25 X) a group of formula (IIIa-10),

30

35

xi) a group of formula (IIIa-11), 40

45

50

xii) a group of formula (IIIa-12),

55

91 EP 2 518 070 A1

5

10 xiii) a group of formula (IIIa-13),

15

20

xiv) a group of formula (Illa-14), 25

30

35 xv) a group of formula (IIIa-15),

40

45

xvi) a group of formula (IIIa-16),

50

55

92 EP 2 518 070 A1

xvii) a group of formula (IIIa-17),

5

10

xviii) a group of formula (IIIa-18),

15

20

25 xix) a group of formula (IIIa-19),

30

35

xx) a group of formula (IIIa-20),

40

45

xxi) a group of formula (IIIa-21), and 50

55

93 EP 2 518 070 A1

5

10 xxii) a group of formula (IIIa-22)

15

20

wherein

25 R18, R22, R23, and R 24 each independently represent a hydrogen atom, a C 1-C4 alkoxy group, a C 1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group, a C 3-C4 cycloalkyl group, a -(CH 2)0-3CN group, a -C (O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a1 -CC4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" each independently represent a 30 hydrogen atom, a hydroxy group, a C 1-C4 alkoxy group or a linear or branched C 1-C4 alkyl group; and wherein Y is as defined in claim 1;

or in the case that Y represents a -NR’- group, R 4 together with the -NR’- group and the carbon atom to which both R4 and the -NR’- group are bonded form a 4- to 7-membered, saturated N-containing heterocyclyl group, which 35 heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group.

12. A compound according to any one of claims 1 or 3 to 8, wherein R5 represents a group selected from

40 i) a group of formula (IIIb-1),

45

50

ii) a group of formula (IIIb-2),

55

94 EP 2 518 070 A1

5

10

iii) a group of formula (IIIb-3),

15

20

iv) a group of formula (IIIb-4), 25

30

35 v) a group of formula (IIIb-5),

40

45

vi) a group of formula (IIIb-6), 50

55

95 EP 2 518 070 A1

5

10

vii) a group of formula (IIIb-7), and

15

20

25 viii) a group of formula (IIIb-8),

30

35

wherein

40 R18, R22, R25, R26, and R27 each independently represent a hydrogen atom, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a 1 C-C4 hydroxyalkyl group, a 3-C C4 cycloalkyl group, a -(CH2)0-3CN group, a -C (O)-(CH2)1-3-CN group, a -C (O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R" group, or a linear or branched C1-C4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a 3 C-C4 cycloalkyl group; wherein R’ and R" each 45 independently represent a hydrogen atom, a hydroxy group, a C 1-C4 alkoxy group or a linear or branched C 1-C4 alkyl group; and wherein Y is as defined in claim 1;

or in the case that Y represents a -NR’- group, R 4 together with the -NR’- group and the carbon atom to which both R4 and the -NR’- group are bonded form a 4- to 7-membered, saturated N-containing heterocyclyl group, which 50 heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group.

13. A compound according to any one of claims 1 or 3 to 8, wherein R5 represents a group selected from

55 i) a group of formula (Illc-1), and

96 EP 2 518 070 A1

5

10

ii) a group of formula (IIIc-2),

15

20

25 wherein

R19, R20, and R28 each independently represent a hydrogen atom, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group, a C 3-C4 cycloalkyl group, a -(CH 2)0-3CN group, a -C (O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl 30 group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a1 -CC4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C 1-C4 alkoxy group or a linear or branched C 1-C4 alkyl group; and wherein Y is as defined in claim 1;

35 or in the case that Y represents a -NR’- group, R 4 together with the -NR’- group and the carbon atom to which both R4 and the -NR’- group are bonded form a 4- to 7-membered, saturated N-containing heterocyclyl group, which heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group.

40 14. A compound according to any one of claims 1 or 3 to 8, wherein R5 represents a group selected from

i) a group of formula (IIId-1),

45

50

55 ii) a group of formula (IIId-2), and

97 EP 2 518 070 A1

5

10

iii) a group of formula (IIId-3),

15

20

25 wherein

R21, R28, R29, and R 30 each independently represent a hydrogen atom, a C 1-C4 alkoxy group, a C 1-C4 haloalkyl group, a C 1-C4 hydroxyalkyl group, a C 3-C4 cycloalkyl group, a -(CH 2)0-3CN group, a -C (O)-(CH2)1-3-CN group, a -C(O)-(CH2)0-3-R’ group, a -C (O)-(CH2)0-3-NR’R", a -(CH 2)0-3NR’R" group, or a linear or branched C 1-C4 alkyl 30 group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a1 -CC4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group; wherein R’ and R" each independently represent a hydrogen atom, a hydroxy group, a C 1-C4 alkoxy group or a linear or branched C 1-C4 alkyl group; and wherein Y is as defined in claim 1;

35 or in the case that Y represents a -NR’- group, R 4 together with the -NR’- group and the carbon atom to which both R4 and the -NR’- group are bonded form a 4- to 7-membered, saturated N-containing heterocyclyl group, which heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a -CHF2 group or a -CF3 group.

40 15. A compound of according to claim 1, which is of fomula (Ia):

45

50

55

wherein R1, R2, R3, R4, R5, R6, Ra, Rb and n are as defined in any one of the preceding claims.

98 EP 2 518 070 A1

16. A compound according to claim 1, which is of fomula (Ib):

5

10

15

wherein R1, R2, R3, R4, R5, Ra, Rb and n are as defined in any one of claims 1 to 14. 20 17. A compound according to claim 1, wherein:

X represents a nitrogen atom or a -CR6 group; Ra and Rb each independently represent a hydrogen atom or a methyl group; 25 R1 represents a methyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridinyl group, a piperidinyl group or a tetrahydropyranyl group; wherein the cycloalkyl, phenyl, pyridinyl, piperidinyl or tetrahydropyranyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-C3 alkyl group, a -NR7R8 group or a -OR 8 group; wherein R 7 and R 8 each independently represent a hydrogen atom or a linear or branched 30 C1-C3 alkyl group; R2 and R3 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group; R4 represents a hydrogen atom, a C1-C3 haloalkyl group, or a linear or branched C1-C3 alkyl group; R6 represents a hydrogen atom, a halogen atom, a C1-C3 haloalkyl group, a linear or branched C1-C3 alkyl group or a cyclopropyl group; 35 R5 represents a group selected from:

i) a group of formula (IIa), which group is a purinyl group unsubstituted or substituted by a -NR’R" group; ii) a group of formula (IIb), which group is selected from a -NH- pyridinyl group, a -S-pyridinyl group, a -NH- pyrimidinyl group or a -S-pyrimidinyl group; wherein the pyridinyl or pyrimidinyl groups are unsubstituted 40 or substituted by one, two or three substituents selected from2) 0-3 aCN -(CH group, a -C (O)-(CH2)0-3-NR’R" or a -(CH2)0-3NR’R" group; and iii) a group of formula (IIc), which group is selected from a -NH- purinyl group or a -S- purinyl group; wherein the purinyl group is unsubstituted or substituted by a -(CH2)0-3NR’R" group; or

45 R4 and R5 together with the carbon atom to which they are attached form a pyrrolidinyl-purinyl group, wherein the purinyl group is unsubstituted or substituted by a -(CH2)0-3NR’R" group; R’ and R" each independently represent a hydrogen atom, a C 1-C3 alkoxy group or a linear or branched C 1-C3 alkyl group.

50 18. A compound according to claim 1, which is one of:

2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Aminopyrimidin-4-ylamino)methyl)-5-chloro-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-5-cyclopropyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 55 2-((6-amino-9H-purin-9-yl)methyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-aminopyrimidin-4-ylamino)methyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 4-((4-Oxo-3-o-tolyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)methylamino)picolinamide; 2-((2-aminopyridin-4-ylamino)methyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one;

99 EP 2 518 070 A1

2-((9H-purin-6-ylamino)methyl)-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-3-cyclohexylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]thazin-4(3H)-one; 2-((9H-purin-6-ylthio)methyl)-5-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 5 2-((6-amino-9H-purin-9-yl)methyl)-6-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((9H-purin-6-ylthio)methyl)-6-methyl-3-o-tolylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-(1-(6-amino-9H-purin-9-yl)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(6-aminopyrimidin-4-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 10 (S)-2-(1-(2-amino-9H-purin-6-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)propylamino)pyrimidine-5-carbonitrile; (R)-2-(1-(9H-purin-6-ylamino)propyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(2-amino-9H-purin- 15 6-ylamino)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(6-aminopyrimidin-4-ylamino)ethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile; 2-(1-(6-amino-9H-purin-9-yl)ethyl)-5-methyl-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 20 2-((6-Amino-9H-purin-9-yl)methyl)-3-o-tolyl-5-(trifluoromethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(3-methoxyphenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(2,4-difluorophenyl)pyrrolo-[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-3-benzyl-5-chloropyrrolo[1,2-f][1,2,4]-triazin-4(3H)-one; 25 2-((6-amino-9H-purin-9-yl)methyl)-3-phenylimidazo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-amino-9H-purin-9-yl)methyl)-3-o-tolylimidazo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(pyridin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6- Amino- 9H-purin- 9- yl) methyl)- 5- chloro- 3-(tetrahydro- 2H- pyran- 4- yl) pyrrolo-[1,2- f] [1,2,4] triazin- 4 (3H)-one; 30 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(1-methylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(9H-Purin-6-ylamino)ethyl)-3-(3-fluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-Amino-6-(1-(3-(3-fluorophenyl)-4-oxo-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine- 5-carbonitrile; (S)-2-(1-(9H-Purin-6-ylamino)ethyl)-3-(3,5-difluorophenyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 35 (S)-4-Amino-6-(1-(3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile; 2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-methylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; 2-((6- Amino- 9H-purin- 9- yl) methyl)- 3-((1r, 4r)- 4- aminocyclohexyl)- 5- chloropyrrolo [1,2- f] [1,2,4] triazin- 4 (3H)-one; 40 (R)-2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(1-phenylethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-((6-Amino-9H-purin-9-yl)methyl)-5-chloro-3-(1-phenylethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(9H-purin-6-yl)pyrrolidin-2-yl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(pyridin-2-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(4-oxo-3-(pyridin-2-yl)-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5- 45 carbonitrile; (S)-4-amino-6-(1-(4-oxo-3-phenyl-5-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile; (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenyl-5-(trifluoromethyl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(5-(difluoromethyl)-4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)ethylamino)py- 50 rimidine-5-carbonitrile; (S)-2-(1-(9H-purin-6-ylamino)ethyl)-5-(difluoromethyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-2-(-(9H-purin-6-ylamino)ethyl)-3-phenylimidazo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydroimidazo[1,2-f][1,2,4]triazin-2-yl)ethylamino)pyrimidine-5-carbonitrile; 55 (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-phenylimidazo[1,2-f][1,2,4]triazin-4(3H)-one; (S)-4-amino-6-(1-(4-oxo-3-phenyl-3,4-dihydroimidazo[1,2-f][1,2,4]triazin-2-yl)propylamino)pyrimidine-5-carbonitrile; 2-(1-(9H-purin-6-ylamino)-3,3,3-trifluoropropyl)-3-phenylpyrrolo[1,2-f][1,2,4]triazin-4(3H)-one;

100 EP 2 518 070 A1

4-amino-6-(3,3,3-trifluoro-1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)propylamino)pyrimidine-5-carbonitrile;

or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof. 5 19. A compound according to any one of claims 1 to 18, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Phosphoinositide 3-Kinase (PI3K).

20. A compound according to claim 19, wherein the pathological condition or disease is selected from respiratory 10 diseases; allergic diseases; inflammatory or autoimmune-mediated; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo- dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors.

15 21. A compound according to claims 19 or 20, wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic kera- 20 tosis.

22. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 18 in association with a pharmaceutically acceptable diluent or carrier.

25 23. Use of a compound as defined in any one of claims 1 to 18, for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in any one of claims 19 to 21.

24. A method for treating a subject afflicted with a pathological condition or disease as defined in any one of claims 19 to 21, which comprises administering to said subject a therapeutically effective amount of a compound as defined 30 in any one of claims 1 to 18, or a pharmaceutical composition as defined in claim 22.

25. A combination product comprising (i) a compound as defined in any one of claims 1 to 18; and (ii) another compound selected from the group consisting of an Adenoside A 2A agonist, an agent for treating cardiovascular disorders, an agent for treating diabetes, and an agent for treating liver disease, an anti- allergic agent, an anti-cholinergic agent, 35 an anti-inflammatory agent, an anti-infective agent, a β2-adrenergic agonist, a Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitor, a chemotherapeutic agent, a corticosteroid, an IKKβ/IKBKB (IkB kinase beta or IKK2) inhibitor, an immunosuppressant, a Janus kinase (JAK) inhibitor, a topically acting p38 Mitogen-Activated Protein Kinase (p38 MAPK) inhibitor, a Phosphosdiesterase (PDE) IV inhibitor, and a Spleen tyrosine kinase (Syk) inhibitor, for simultaneous, separate or sequential use in the treatment of the human or animal 40 body.

45

50

55

101 EP 2 518 070 A1

102 EP 2 518 070 A1

103 EP 2 518 070 A1

104 EP 2 518 070 A1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

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